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Cancer Research
at DKFZ
2014
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2014
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GERMAN CANCER RESEARCH
CENTER IN THE HELMHOLTZ
ASSOCIATION
Cancer Research
at DKFZ
2014
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Welcome
to the German Cancer Research Center
Josef Puchta (left), Chancellor Angela Merkel and Otmar D. Wiestler.
With “Cancer Research at DKFZ”, we would like to introduce the DKFZ (Deutsches Krebsforschungszentrum),
Germany´s largest biomedical research center whose mission is to fight cancer through research. More than 3000
staff members, including 1000 scientists, contribute to unraveling the basic mechanisms that lead to cancer, identifying cancer risk factors, developing cancer prevention strategies, as well as translating our results from bench to
bedside in order to improve cancer diagnosis, therapy and prevention.
Cancer is a worldwide burden, with approximately 14.1 million new cases each year and around 8.2 million deaths
from cancer. The disease constitutes a particularly challenging task for both research and clinical practice. There are
more than 200 different cancer entities in almost every organ in the human body. The changes in affected cells are
highly diverse and complex.
In 2014, DKFZ is celebrating its 50th anniversary. We are very happy and proud that Chancellor Angela Merkel visited
our center on April 23 in honor of this celebration. She was impressed by the major contributions researchers at DKFZ
have made in recent years: We understand much better today how cancer develops; we diagnose the disease earlier,
treat it better, and prevent it more effectively. In 2008, Harald zur Hausen, the long-standing director of the management board at DKFZ, was awarded the Nobel Prize for Medicine. He had discovered that human papillomaviruses
cause cervical cancer, which led to the development of a vaccine that is now available worldwide.
Perhaps you too would like to be part of this unique institution at the cutting edge of cancer research. “Cancer Research at DKFZ" gives you a taste of what research is like in our center. Come and join us as a PhD student, Post Doc,
group leader or as a full Professor. We look forward to welcoming you to our institution.
Best wishes
Prof. Dr. Dr. h. c. Otmar D. Wiestler
Chairman and Scientific Director
Prof. Dr. Josef Puchta
Administrative-Commercial Director
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Contents
DKFZ – The German Cancer Research Center______________6
NCT – National Center for Tumor Diseases Heidelberg______9
The German Consortium for Translational
Cancer Research____________________________________ 10
Nobel Prize in Medicine 2008 - Harald zur Hausen________ 12
DKFZ Life-Science Lab________________________________ 14
Graduate Studies at the DKFZ_________________________ 15
Cancer Information Service___________________________ 16
Unit Cancer Prevention_______________________________ 17
Heidelberg – A Capital of Biomedical Sciences in Europe___ 20
CORE FACILITIES_________________________________________ 23
Genomics and Proteomics____________________________ 24
Imaging and Cytometry______________________________ 25
Information Technology______________________________ 26
Animal Laboratory Services___________________________ 27
Library_____________________________________________ 28
Joint Chemical Biology Core Facility of EMBL & DKFZ______ 29
Index_____________________________________________ 142
Imprint___________________________________________ 143
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RESEARCH PROGRAMS_________________________ 31
Cell Biology and Tumor Biology_______________________ 32
Stem Cells and Cancer_______________________________ 34
Molecular Embryology_______________________________ 35
Signal Transduction and Growth Control _______________ 36
Epigenetics_________________________________________ 38
Systems Biology of Cellular Signal Transduction__________ 39
Redox Regulation___________________________________ 40
Molecular Metabolic Control _________________________ 41
Vascular Oncology and Metastasis _____________________ 42
Cell Growth and Proliferation _________________________ 43
Clinical Neurobiology ________________________________ 44
Chaperones and Proteases ___________________________ 45
Molecular Neurobiology _____________________________ 46
Molecular Biology of the Cell II________________________ 47
Cell Biology ________________________________________ 48
Molecular Biology of the Cell I ________________________ 49
Molecular Biology of Centrosomes and Cilia_____________ 50
Posttranscriptional Control of Gene Expression __________ 51
Cellular Senescence_________________________________ 52
Normal and Neoplastic CNS Stem Cells _________________ 53
Vascular Signaling and Cancer_________________________ 54
Stress-induced Activation of Hematopoietic Stem Cells____ 55
Experimental Hematology____________________________ 56
Biomarker identification______________________________ 57
Metastatic Niches___________________________________ 58
Synaptic Signalling and Neurodegeneration_____________ 59
Structural and Functional Genomics ________________ 60
Tumor Genetics_____________________________________ 62
Biophysics of Macromolecules_________________________ 63
Molecular Genome Analysis__________________________ 64
Molecular Genetics _________________________________ 65
Pediatric Neurooncology _____________________________ 66
Functional Genome Analysis __________________________ 67
Theoretical Bioinformatics ___________________________ 68
Theoretical Systems Biology __________________________ 69
Signaling and Functional Genomics ____________________ 70
Signal Transduction in Cancer and Metabolism __________ 72
Molecular RNA Biology and Cancer_____________________ 73
Membrane Biophysics _______________________________ 74
Systems Biology of Cell Death Mechanisms______________ 75
Proteostasis in Neurodegenerative Disease______________ 76
Lysosomal Systems Biology ___________________________ 77
Cancer Risk Factors and Prevention__________________ 78
Epigenomics and Cancer Risk Factors___________________ 80
Cancer Epidemiology ________________________________ 81
Molecular Genetic Epidemiology______________________ 82
Biostatistics________________________________________ 83
Clinical Epidemiology and Aging Research_______________ 84
Molecular Epidemiology______________________________ 85
Tumor Immunology____________________________________ 86
Translational Immunology ___________________________ 88
Immunogenetics____________________________________ 89
Molecular Immunology______________________________ 90
Developmental Immunology _________________________ 91
Cellular Immunology ________________________________ 92
Innate Immunity____________________________________ 93
Immune Tolerance___________________________________ 94
Imaging and Radiooncology__________________________ 96
Radiology__________________________________________ 98
Medical Physics in Radiology__________________________ 99
Radiopharmaceutical Chemistry _____________________ 100
Medical Physics in Radiation Oncology ________________ 101
Radiation Oncology_________________________________ 102
Molecular Radiooncology____________________________ 103
Nuclear Medicine __________________________________ 104
Medical and Biological Informatics ___________________ 105
Optical Nanoscopy _________________________________ 106
Translational Radiation Oncology_____________________ 108
Computer-assisted Interventions_____________________ 109
Infection and Cancer__________________________________ 110
Tumorvirology_____________________________________ 112
Genome Modifications and Carcinogenesis_____________ 113
Viral Transformation Mechanisms ____________________ 114
Characterization of Tumorviruses_____________________ 115
Pathogenesis of Virus Associated Tumors______________ 116
Oncolytic Adenoviruses_____________________________ 117
Noroviruses_______________________________________ 118
Infection and Innate Immune Sensing Dynamics________ 119
Translational Cancer Research_______________________ 120
Translational Oncology _____________________________ 122
Applied Tumor Biology ______________________________ 123
Preventive Oncology _______________________________ 124
Cellular and Molecular Pathology _____________________ 125
Molecular Tumor Pathology _________________________ 126
Dermato-Oncology _________________________________ 127
Molecular Hematology/Oncology ____________________ 128
Pediatric Oncology _________________________________ 130
Molecular Oncology of Solid Tumors___________________ 131
Molecular Oncology of Gastrointestinal Tumors_________ 132
Neurooncology____________________________________ 134
Neuropathology___________________________________ 135
Experimental Neuroimmunology_____________________ 136
Experimental Therapies for Hematologic Malignancies___ 137
Molecular Mechanisms of Tumor Cell Invasion__________ 138
Neuropeptides_____________________________________ 139
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DKFZ
The German Cancer
Research Center
The German Cancer Research Center (DKFZ) is one of the world’s
leading biomedical research institutions. It serves the mission to
identify and study cancer risk factors and to unravel mechanisms
of cancer development. The findings from our basic research are
systematically employed to develop new approaches for prevention, diagnosis and treatment.
Employees: 2763
Staff Scientists: 878
Doctoral students: 384
Scientists from 63 nations
(as of December 2013)
The German Federal Government provides 90 percent of the
funding of the German Cancer Research Center, and the State of
Baden-Württemberg the remaining 10 percent. Additional income
stems from external project funding, license revenues, donations
and bequests.
The 47 scientific divisions, 28 junior research groups and 13 clinical
cooperation units are assigned to seven Research Programs:
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Cell Biology and Tumor Biology
Functional and Structural Genomics
Cancer Risk Factors and Prevention
Tumor Immunology
Imaging and Radiooncology
Infection and Cancer
Translational Cancer Research
Jointly with Heidelberg University Hospital, DKFZ has established
the National Center for Tumor Diseases (NCT) Heidelberg where
promising approaches from cancer research are translated into the
clinic.
The Cancer Information Service (KID) provides cancer patients, their
families, and other interested parties with information that is readily understandable, scientifically founded, impartial, and up to date.
In 2011, the German Consortium for Translational Cancer Research
was introduced to the public by the BMBF, the German Federal
Government, as one of six German Centers for Health Research.
This initiative intends to foster the nationwide strategic collaboration of the most excellent scientists and clinicians in exploring
common cancer diseases.
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DKFZ Main Building
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DKFZ
The German Cancer
Research Center
“ATV” Building
In the applied tumor virology building
scientists work with viruses that cause
cancer, such as HPV oder EBV, but also
with viruses that infect and kill cancer
cells, such as the oncolytic parvoviruses.
“TP3” Building
This building, completed in 2002, is
where genome research takes places.
This so-called “Genome-Building” harbors
the DKFZ´s sequencing facility with 15
high-throughput next generation DNA
sequencing instruments. It also houses
servers with a data storage capacity of
10 terabytes, 1.2 terabytes of which is
reserved for the three German projects
in the International Cancer Genome
Consortium.
“TP4” Building
This building in the technology park of
the Neuenheim Campus was acquired in
2007 and provides additional space for
320 people.
7T MRI Building
As part of the strategic alliance with
Siemens, a 7T MRI system was installed
in a new facility. Thirty tons of steel
included in the surrounding walls shield
the ultra high magnetic field from the
environment.
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NCT
National Center for
Tumor Diseases Heidelberg
Initiated in 2004, and actively treating patients
since 2005, the National Center for Tumor Diseases (NCT) Heidelberg was founded as an exceptional alliance between the German Cancer
Research Center (DKFZ), Heidelberg University
Medical School (HUMS) together with Heidelberg Medical Faculty and German Cancer Aid
(Deutsche Krebshilfe). NCT is a comprehensive
cancer center uniquely positioned to benefit
from the wealth of DKFZ cancer research and
the Heidelberg biomedical campus. NCT’s mission is two-fold: to provide optimal interdisciplinary oncology with current clinical therapies
and to rapidly transfer scientific knowledge
into clinical applications through comprehensive translational and preventive oncology.
The new 5500 m2 NCT Core Building has been
completed in 2010.
NCT is the principal portal of entry for all
oncology patients into the medical center, and
the primary location of all oncology outpatient
care. It integrates and supports all clinical and
translational research activities of DKFZ and
HUMS. DKFZ’s many scientific disciplines and
interactions, including strategic partnerships
with university medical centers and industry,
provide a strong framework for NCT projects.
Research at DKFZ 2014
In 2012, approx. 11,000 newly diagnosed cancer
patients were seen at NCT and more than
18,000 anti-tumor therapies were administered. With more than 50,000 out-patient
visits p.a., patient numbers are steadily growing. More than 300 diagnostic, therapeutic and
preventive clinical trials, including investigator
initiated trials, were developed and conducted.
NCT pursues personalized oncology as a
center-wide master strategy that coordinates
all activities towards individualized cancer
medicine, including patient-oriented genetics,
proteomics, radiooncology, immunology and
prevention. The recently established Heidelberg Center for Personalized Oncology (DKFZHIPO) forms a dedicated genomics, proteomics
and bioinformatics platform of DKFZ, enabling
excellent basic and translational research. Its
clinical counterpart, the NCT Precision Oncology Program (NCT POP) combines molecular
diagnostics, innovative therapeutics development, interdisciplinary patient care and prevention to define molecularly stratified patient
cohorts and hypothesis-driven treatments.
Towards this goal, the center aims to provide
comprehensive high-throughput genetic and
molecular analysis as a stratification tool for
every NCT patient by 2015.
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DKTK
The German Consortium for
Translational Cancer Research
The DKTK Steering Committee (from left to right):
Josef Puchta (Heidelberg), Christoph Peters (Freiburg), Otmar D. Wiestler (Heidelberg), Christian Peschel (Munich), Reinhold Schäfer (Berlin), Wolfgang
Hiddemann (Munich), Christof von Kalle (Heidelberg), Martin Schuler (Essen/Düsseldorf), Michael
Baumann (Dresden), Hubert Serve (Frankfurt),
Klaus Schulze-Osthoff (Tübingen)
Successful cancer research necessitates intensive exchange between very differing specialties. For this reason, cancer research often
takes place at very large centers; in the USA in
some incidences they have over 10,000 staff
members.
The German Cancer Consortium reaches a
critical mass in another way, by establishing
long term links between the German Cancer
Research Center in Heidelberg and some of the
largest university hospitals in Germany. Currently, some twenty institutions are cooperating at eight different sites.
Seven programs in the fight against cancer
A core function of cancer research is the
continuous review of fundamental research
results to identify new targets for prevention,
diagnosis and treatment of cancer diseases.
More than 420 physicians, scientists and their
groups in the DKTK are committed to this
“translational” concept.
There are seven defined research programs,
in each of which an increasing number of
sites are participating:
Joint platforms harness strengths
The joint research work within DKTK is vitally
supported by five platforms providing the
necessary infrastructure for the Consortium. A
core element is the “Clinical Communication
Platform“. It allows the recruitment of patients
at all sites and also serves as a shared pivot in
innovative clinical trials.
In addition, there will be technically oriented
platforms. The aim is to harmonize the technical requirements over all sites to ensure
comparable data and to provide a common
structure allowing scientists from all locations
access to methods that would otherwise be
unavailable.
Attractive offers for junior researchers
In cancer research it is essential that different disciplines pull together. Accordingly, a
broad program to develop junior researchers is
extremely important. Young medical doctors,
especially those with some clinical experience
are offered the opportunity of training in cancer
research at the “School of Oncology”. Likewise,
researchers with a background in natural sciences will be introduced to translational research.
| Oncogenic Pathways
| Molecular Diagnostics
| Cancer Immunology and Immunotherapy
| Stem Cells in Oncology
| Radiation Oncology and Imaging
| Treatment Resistance
| Cancer Prevention, Early Detection,
and Outcomes
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The individual research platforms are:
| Clinical Communication Platform
| GMP and Core Services
| Preclinical Models
| Drug Development
| School of Oncology
The DKTK Partner Sites
DKTK Berlin
Charité Comprehensive Cancer Center, Berlin
PROFESSOR DR. REINHOLD SCHÄFER
DKTK Dresden
Medical Faculty and University Hopsital Carl Gustav
Carus, Max-Planck-Institute for Molecular Cell
Biology and Genetics, Helmholtz Research Center
Dresden-Rossendorf
PROFESSOR DR. MICHAEL BAUMANN
DKTK Essen/Düsseldorf
Westdeutsches Tumorzentrum of the University
Hospital Essen, Heinrich Heine-University Düsseldorf
PROFESSOR DR. MARTIN SCHULER
DKTK Frankfurt/Mainz
University Cancer Center Frankfurt, GoetheUniversity Frankfurt, Georg-Speyer-Haus, Frankfurt,
Krankenhaus Nordwest, Frankfurt, University Medical
Center, Mainz
PROFESSOR DR. HUBERT SERVE
DKTK Freiburg
University Medical Center of the Albert-LudwigsUniversity Freiburg, Max-Planck-Institute of
Immunobiology, Freiburg
PROFESSOR DR. CHRISTOPH PETERS
DKTK Heidelberg (Core Center)
German Cancer Research Center Heidelberg (DKFZ),
Heidelberg University Medical School, National
Center for Tumor Diseases (NCT), Heidelberg;
Associated Partner: Paul-Ehrlich-Institute, Langen,
University of Cologne
PROFESSOR DR. DR. H.C. OTMAR WIESTLER,
PROFESSOR DR. JOSEF PUCHTA
DKTK Munich
Ludwig-Maximilians University Munich,
Technische Universität Munich
PROFESSOR DR. WOLFGANG HIDDEMANN
DKTK Tübingen
Faculty of Medicine and University Hospital, Eberhard
Karls University of Tübingen, Fakulty of Life Science,
Eberhard Karls Universität Tübingen
PROFESSOR DR. KLAUS SCHULZE-OSTHOFF
The second DKTK-Retreat on May 12th and
13th 2014 was a full success. More than
300 persons participated.
Research at DKFZ 2014
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Nobel Prize
in Medicine
2008
Harald zur Hausen
The idea was revolutionary back in 1972.
Flying in the face of prevailing expert
opinion, Harald zur Hausen hypothesized
that the viruses that cause warts might
also play a role in the development of
cervical cancer.
Supplying the evidence turned out to be
more difficult than he had anticipated. In
1983, however, after years of relentless
searching, zur Hausen and his team
at last succeeded in isolating the DNA
of this pathogen, also known as human
papillomavirus (HPV), in a biopsy. What
they had found was HPV16, a hitherto
unknown representative of the large and
complex family of papillomaviruses. In
the following years, it transpired that
the two high-risk virus types HPV16
and HPV18 are responsible for around
70 percent of all cases of cervical cancer
worldwide. A total of 15 of the 170 HPVs
so far identified have been shown to be carcinogenic. The DNA of papillomaviruses is found
inmore than 99 percent of all tissue samples
taken from women with cervical cancer.
This type of cancer affects around half a
million women every year. The disease
often ends in death, especially in Third
World countries which cannot afford cancer
screening programs.
Following their discovery of carcinogenic
papillomaviruses, zur Hausen and his
team studied how the pathogens survive
in the cell and how the cells eventually
mutate into cancer. It was their understanding of the biology of infection that
enabled them to develop a vaccine to
protect women against cervical cancer.
Harald zur Hausen served as Chairman of the
German Cancer Research Center from
1983 to 2003. In 2008, he was awarded the
Nobel Prize in Medicine in honor of his
outstanding contribution to science.
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Press conference on October 6, 2008 in the DKFZ Communication Center.
Research at DKFZ 2014
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DKFZ Life-Science Lab:
A place where students can think and experiment
The Life-Science Lab which has been established at DKFZ offers extracurricular opportunities to talented middle and senior high
school students with a particular interest in
math and science. Here, the focus is on those
areas in the life sciences in which research is
being conducted at DKFZ and partner institutions.
In addition to helping the students to develop
interdisciplinary competence and to achieve
personal goals that are educationally significant, they are also encouraged to work
independently and to take responsibility for
research activities so as to experience the
pleasure of discovery and to learn how to collaborate constructively.
The multi-year program is organized into six
areas of activities:
1. Public Friday lectures on scientific, theoretical, and philosophical topics aim to
awaken curiosity in the students.
2. Core research work takes place in
scientist-mentored work groups in the
fields of archeology, astrophysics, chemistry, experimental physics, informatics,
climatology, art, mathematics, molecular
cell biology, neuropsychology, medicine,
pharmacy, philosophy, political science,
quantum physics, robotics, synthetic biology, systems biology, theoretical physics,
commerce, and zoology.
3. Weekend seminars present opportunities to broaden the scope of work group
research.
4. (Inter)National summer academies, for
example, internships lasting for several
weeks as research fellows at the universities of Stanford and Berkeley, afford
Participants in the robotics seminar construct a
robot together with doctoral candidates from
Kaiserslautern University (picture above).
High school students work to obtain their „Lab
License“ at the Bio-Science Lab (picture in the
middle).
Good attendance at one of the weekly Friday lectures (picture below).
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5.
6.
opportunities to put the acquired competence into an international context.
The Bio-Science Lab and Phys-Tech Lab
give depth to the broad theoretical
instruction in the areas of biochemistry,
molecular and cell biology, as well as in
physics and technology, through both
mentor-initiated and independent practical laboratory work.
Research projects performed under
scientific guidance promote the successful development of ideas or separate
subprojects and facilitate self-organized
and exploratory learning.
Successful applicants may participate from
eighth grade through to high school graduation. Students in their final year of school share
their experience by acting as student mentors.
Since 2005, the Alumni Association has been
bringing former participants together, which
furthers networking.
Of particular significance is the integration
into genuine research through the participation of scientific mentors from DKFZ, EMBL,
the universities of Heidelberg, Mannheim, Kaiserslautern, and Landau as well as from Max
Planck Institute, Heidelberg. The Life-Science
Lab is further supported by cooperation partners from business and public sectors.
In 2009, the Life-Science Lab won First Prize
in the competition ”School meets Science”
sponsored by the Robert-Bosch Foundation for
its model character, while in 2010 the Initiative
“Germany – Land of Ideas” awarded the Lab
the status “Designated Site of Ideas”.
Dr. Katrin Platzer
Life-Science Lab
DKFZ
Im Neuenheimer Feld 581
69120 Heidelberg
Phone: +49 6221/4214-01
Fax: +49 6221/4214-10
[email protected]
www.life-science-lab.org
Graduate Studies at the DKFZ
Helmholtz International Graduate School
for Cancer Research
The Helmholtz International Graduate School
for Cancer Research is the PhD Program of the
German Cancer Research Center. The Graduate
School has approximately 500 members, from
all divisions and research groups of the center.
Through the Graduate School, PhD students
receive world-class training in interdisciplinary
cancer research in preparation for a successful
career in science.
Members are recruited bi-annually from
around the world through a highly competitive and stringent selection procedure. A core
feature of the Graduate School is committed
to scientific supervision of graduate students
through annual Thesis Advisory Committees
(TACs), consisting of the student’s PhD supervisor and at least two other senior scientists,
one of whom is external to the German Cancer
Research Center. The TAC meetings monitor the student’s progress, offer feedback on
research already conducted and discuss any
other issues, which might be relevant to the
student’s work.
Graduate students are further supported
through a comprehensive training program,
starting with a one-week “initial course” during the first months of their PhD and further
professional training throughout their PhD
through scientific and soft-skills courses,
lecture series and careers seminars. Each student also takes part in the graduate studentorganized PhD retreat in their second year,
including, in addition to a scientific program,
career talks external speakers and talks from
student guests of international collaborating
institutes. The program of the Graduate School
therefore ensures that throughout the PhD,
scientific supervision, networking and coopera-
Research at DKFZ 2014
tion between graduate students and leading
scientists is facilitated at an international level.
A further branch of graduate education, the
German-Israeli Helmholtz Research School
in Cancer Biology was established in 2012 in
collaboration with the Weizmann Institute
of Science in Rehovot, Israel. Research School
graduate students work on joint scientific
projects and are jointly supervised by a senior
scientist from both the German Cancer
Research Center and the Weizmann Institute.
All projects include an extended research stay
at the partner institute, during which time
the graduate students have full access to the
resources and services of the partner through
integration into the respective graduate
schools. Annual meetings, joint workshops and
on-going seminar series and courses of the
Research School ensure a continuous exchange
between the partners.
If you are interested in finding out more about
the opportunities for graduate studies at the
German Cancer Research Center, then please
visit our website: www.dkfz.de/phd
Manager of the Graduate and Research
Schools: Dr. Lindsay Murrells
Contact: [email protected]
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Cancer Information Service
National Reference Center for Cancer Information
The Staff
Physicians who have received special training
in health communication answer telephone
and email inquiries. Science journalists and
scientific staff from the areas of medicine,
pharmacy, biosciences and psychology are
responsible for literature and information
searches and editing.
The Cancer Information Service has been
established at the German Cancer Research
Center since 1986. Its aim is to offer up-to-date
cancer information to cancer patients, their
families and friends, and to other interested
members of the public in Germany. Additionally, the service reaches out to health professionals involved in the care and support of
cancer patients.
The Cancer Information Service answers individual questions on all cancer-related topics:
causes and risk factors, prevention and early
detection, diagnosis, treatment and followup care. In addition, the Cancer Information
Service supplies contact details of institutions and organizations involved in medical
and psychosocial care and support of cancer
patients. All information is evidence-based,
comprehensive, readily understandable and
tailored to individual needs. Publicly funded
by the Federal Ministry of Education and Research, the service’s information is neutral and
independent.
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The Cancer Information Service can be reached
through different channels – via telephone,
e-mail and its very informative up-to-date
homepage. The service also issues various brochures and fact sheets on relevant topics. At
the National Center for Tumor Diseases (NCT)
Heidelberg and at the University Cancer Center
(UCC) Dresden, the Cancer Information Service
offers face-to-face counseling.
• The telephone service is available daily
from 8 a.m. to 8 p.m. at +49 6221 999
8000. Calls within Germany (Phone: 0800
420 30 40) are toll-free.
• All email inquiries to [email protected] or via the secured e-mail
form on the website are answered within
two working days.
• On its website www.krebsinformationsdienst.de, the Cancer Information Service
provides information on a multitude of
topics: new research findings, up-to-date
scientific knowledge in oncology, useful
tips for cancer patients, contact information, and links to further quality assured
information resources.
Prospects
The high demand for quality assured cancer
information will continue to grow due to demographic trends, rising cancer incidence and
the introduction of novel clinical therapeutic
options.. Particular emphasis is placed on the
development of special information offerings
for health professionals. Both strong integration into the German Cancer Research Center
and utmost commitment to evidence-based,
quality-tested cancer information are prerequisites for the development of the Cancer
Information Service into a National Reference
Center for Cancer Information.
Performance Figures 2012
Inquiries answered total 29,371
By telephone 23,682
By email 3,737
By telephone and email 485
Letters 1,379
Face-to-face counseling 88
Website visitors per month 230,000 in average
Cancer Information Service
Head of Division:
Dr. Susanne Weg-Remers
Phone: +49 6221 999 8000
Phone: 0800 420 30 40
Daily from 8 a.m. to 8 p.m.
Toll-free within Germany
[email protected]
www.krebsinformationsdienst.de
Unit Cancer Prevention
WHO Collaborating Centre for Tobacco Control
In 2002, the Cancer Prevention unit was designated a World Health Organization Collaborating Centre (WHO-CC) for Tobacco Control, with
the objective of making a noticeable contribution to national and international efforts to
curb tobacco consumption. Its three main aims
are to prevent the onset of smoking, to help
smokers to quit, and to protect the population
against secondhand smoke.
Since the establishment of the WHO-CC, several
measurable results have been achieved. Legislation for the protection of non-smokers from
secondhand smoke was introduced; one Federal
Law and 16 State Laws in 2007/2008 are based
on the Centre’s scientific groundwork.
Several other national tobacco control policies
have been implemented, for which the WHOCC for Tobacco Control developed recommendations.
Furthermore, the WHO-CC for Tobacco Control
elaborated guidelines for implementation of
Article 12 (education, communication, training
and public awareness) of the WHO Framework
Convention on Tobacco Control (WHO-FCTC).
In order to increase the evidence base for
tobacco control policies, the WHO-CC collaborates with the International Tobacco
Control Policy Evaluation Project (ITC). As an
ongoing cohort study, the ITC project follows
smokers and non-smokers for several years
and can thus monitor the effects of tobacco
control measures on individual attitudes and
behaviour.
Significant accomplishments of the past years:
The WHO-CC:
• demonstrated that in 2007, 106,623
deaths were attributable to cigarette
smoking in Germany and that there
was a north-south gradient regarding the tobacco-attributable mortality rate (Gesundheitswesen 2010,
doi:10.1055/s-0030-1252039).
• showed that numerous tobacco additives
are increasing the attractiveness and
palatability of cigarettes as well as the
health risks of smoking (SCENIHR. Addictiveness and attractiveness of Tobacco
Additives.12 November 2010, http://
ec.europa.eu/health/scientific_committees/emerging/docs/scenihr_o_031.
Research at DKFZ 2014
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pdf; Public Information Tobacco Control
(PITOC), http://www.dkfz.de/de/tabakkontrolle/PITOC_Additives_in_Tobacco_
Products.html).
published data on menthol capsules in
cigarette filters showing that they are attractive to young people, thus promoting
smoking initiation. Based on this scientific
evidence a German court prohibited the
introduction of cigarettes with menthol
capsules on the German market (German
Cancer Research Center (Ed.), Menthol
Capsules in Cigarette Filters – Increasing
the Attractiveness of a Harmful Product,
Heidelberg, Germany, 2012; Verwaltungsgericht Braunschweig (2012) Urteil
Az. 5 A 206/11).
showed that public smoking bans promote smoking reduction at home (Mons
U, Nagelhout GE, Allwright S, Guignard R,
van den Putte B, Willemsen MC, Fong GT,
Brenner H, Pötschke-Langer M & Breitling
LP (2013) Impact of national smoke-free
legislation on home smoking bans:
findings from the International Tobacco
Control Policy Evaluation Project Europe
Surveys. Tob Control 22(e1): e2-9).
disclosed the German Cigarette Industry
Organization’s role in obstructing the development and implementation of effective tobacco control policies in Germany
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(Gesundheitswesen 2008, 70:315-24).
published the first National Tobacco Atlas
Germany 2009, an illustrative education
handbook on the social, health and economic aspects related to tobacco and its
use (Tabakatlas Deutschland 2009, 2009,
Steinkopff Verlag).
published German language text and comments, in collaboration with the German
Ministry of Health, on the WHO Framework
Convention of Tobacco Control and recommendations for Germany (Perspektiven für
Deutschland: Das Rahmenübereinkommen
der WHO zur Eindämmung des Tabakgebrauchs – FCTC, 2011, DKFZ).
published the first report worldwide on
e-cigarettes showing the ambivalent
character of these products (German Cancer Research Center (Ed.), E-cigarettes – an
overview. Heidelberg, Germany, 2013).
German Cancer Research Center
Unit Cancer Prevention
WHO Collaborating Centre for Tobacco Control
Head of Department:
Dr. Martina Pötschke-Langer
Im Neuenheimer Feld 280
D-69120 Heidelberg
Phone: +49 6221-423008
Fax : +49 6221-423020
[email protected]
17
DKFZ Career Service
Scientific Life beyond the Lab
The DKFZ Career Service aims to support all
Masters, PhD students and postdocs at DKFZ in
the planning of their professional future. The
Career Service provides career-related workshops and conferences, personal coaching and
advice, and expansion of the career network
by following up with scientists after their stay
at DKFZ. Sharing experience with scientists in
academia, industry and beyond is a great help
to make informed decisions about one’s own
career.
At career days PhD students and postdocs, with
the support of the Career Service, invite scientists with interesting career paths for a short
presentation and panel discussion. Further
career seminars are coordinated together with
other Heidelberg institutions so that, at least
once per year, it is possible to meet scientists with careers in academia, industry, R&D,
consulting, publishing, research management,
patenting, teaching, etc.
The Career Service organizes workshops on
e.g., application skills, CV writing, networking
“Career Plan B (Life/Work Planning)”, soft skills,
business for scientists etc. A detailed overview
can be found in the chapter “Scientific Career
Development/Service” in the DKFZ Advanced
Training Program.
PhD students and postdocs from DKFZ can
make an appointment for a personal and confidential conversation of 45 minutes with our
Career Advisor, Dr. Barbara Janssens. There they
can discuss their specialty, competencies, possibilities and career planning. Furthermore, they
can get information on how and where to look
for professional possibilities, application advice,
or preparation for their application or interview.
18
You are very welcome to join the DKFZ Alumni
Network both while working at DKFZ and after
leaving. You can apply for a free email address
which will forward messages to your private
email, so you can be contacted under first.
[email protected].
Additionally, we warmly invite you to join our
DKFZ group on the professional social media
network LinkedIn. This is a group of current
and past members of the DKFZ where you can
search and connect with scientists working in
an area that interests you. Search for the group
“DKFZ Career Network” on LinkedIn and join
this open group and, relevant to your status,
request membership of the subgroup “Currently@DKFZ” or “DKFZ Alumni”.
Finally, the career service supports extensive
yearly surveys from and for PhD students
and postdocs to ascertain the status quo,
questions and needs concerning young
researchers´scientific careers.
Career Manager: Dr. Barbara Janssens is
Belgian (PhD in molecular/cell biology Ghent
University), did a postdoc in Paris and worked
five years as an editor at Wiley-Blackwell.
Project Coordinator: Marion Gürth studied
biology at the TU Darmstadt, worked as a Research Assistant at Heidelberg University and
as a freelance website translator.
Office H1.06.015b (15b 6th floor main building
west) at the Graduate Program Office M070
www.dkfz.de/careers
Technology Transfer at DKFZ –
From Patents to Products to Patients
The Office of Technology Transfer at DKFZ
works at the interface between research and
industry, building relationships between academic and industrial partners, e.g. collaboration agreements, license agreements and spinoffs. Founded in 1997 and headed by molecular
biologist Dr. Ruth Herzog, the office is tasked
with accelerating innovations that will create
value from DKFZ’s research for the benefit of
society and patients. The team supports DKFZ
scientists in patenting and finding a suitable
industrial partner for their new inventions
and projects. The options chosen, in consultation with the scientist, may involve licensing,
collaborating with established companies or
starting a new company. As a rule, revenues
from licenses are shared with the inventors
and plowed back into cancer research.
Ruth Herzog explains: “Only with patented
inventions can we get partners to invest in
developing DKFZ’s technologies into drugs,
medical products or instruments. Pharma
partners in particular must be able to count on
the exclusivity they get from patent protection to recoup the huge sums they spend on
research and clinical development of a new
cancer drug.”
Although the failure rate in this business is
high (due to high costs and tough competition), the Office has helped to produce a
number of success stories:
1. DKFZ was instrumental in developing a
vaccine to prevent cancer
Two vaccines provide protection against
human papilloma viruses associated
with the development of cervical cancer
and are the DKFZ’s best known invention to date. Professor Harald zur Hausen
was awarded the 2008 Nobel Prize for
Medicine for research that led to this
development.
2. DKFZ’s research has produced spin-off
companies
Spin-offs are important partners paving
the road to commercialization. Take MTM
laboratories AG, for instance. This publicly
traded company for in vitro diagnostics
Research
Research
at DKFZ
at DKFZ
2013/2014
2014
3.
was acquired by Roche in 2011 and is now
part of the Roche Tissue Diagnostics unit
(Ventana Medical Systems, Inc.). Apogenix, another DKFZ spin-off and a biopharmaceutical company developing novel
protein therapeutics for the treatment of
cancer and inflammatory diseases, has
successfully completed the phase II study
for its lead compound Apocept™ for the
second line treatment of glioblastoma.
DKFZ has built strategic alliances with
industry
The strategic and translational alliance
with Bayer Healthcare draws on the
strengths of both partners and thus
accelerates the process from “bench to
bedside”. Recently, DKFZ and Bayer agreed
to work more closely together in the field
of immunotherapy in a joint laboratory
in Heidelberg. Equally important is the
alliance with Roche and the Heidelberg
University Hospital in the field of personalized medicine, in a venture that spans
research collaboration and clinical studies.
Dr. Ruth Herzog, M.A., CLP
Creating value from research.
Head of the Office of Technology Transfer
Phone: +49 6221/42-2955
Fax: +49 6221/42-2956
[email protected]
19
Heidelberg
A Capital of Biomedical Sciences
in Europe
In the charming city of Heidelberg with
its biomedical Campus Neuenheim
DKFZ is surrounded by strong partner
institutions.
20
Heidelberg University
Heidelberg University, founded in 1386, is
Germany’s oldest university and one of the
strongest research universities in Europe. The
successes in both rounds of the Excellence
Initiative and in international rankings prove
its leading role in the scientific community. In
terms of educating students and promoting
promising young academics, Heidelberg relies
on its two strongest points: research-based
teaching and outstanding, well-structured
training for doctoral candidates.
Heidelberg University is a comprehensive
university with the full spectrum of subjects
including medicine. It aims to strengthen the
individual disciplines, to further interdisciplinary cooperation and to carry research results
over into society and industry. Heidelberg also
draws its strength from its cooperation with
local non-university research institutions such
as the DKFZ and the Max Planck Institutes. In
addition, the university is tied into a worldwide
network of research and teaching collaborations which give evidence of its marked global
interconnectedness.
Heidelberg University Hospital and
Medical Faculty
Heidelberg University Hospital is one of the
largest and most prestigious medical centers
in Germany. The Medical Faculty of Heidelberg
University belongs to the internationally most
renowned biomedical research institutions in
Europe. Both institutions have the common
goal of developing new therapies and implementing them rapidly for patients. With about
11,000 employees, training and qualification is
an important issue. Every year, around 118,000
patients are treated on an inpatient basis and
around 1.000.000 cases on an outpatient basis
in more than 50 clinics and departments with
2,200 beds. Currently, about 3,500 future physicians are studying in Heidelberg; the reform
Heidelberg Curriculum Medicinale (HeiCuMed)
is one of the top medical training programs in
Germany.
European Molecular Biology
Laboratory Heidelberg
The European Molecular Biology Laboratory
is a basic research institute funded by public
research monies from 20 member states and
associate member state Australia. Research
at EMBL is conducted by approximately 85
independent groups covering the spectrum
of molecular biology. The Laboratory has five
units: the main Laboratory in Heidelberg, and
Outstations in Hinxton (the European Bioinformatics Institute), Grenoble, Hamburg, and
Monterotondo near Rome. The
cornerstones of EMBL’s mission are: to perform
basic research in molecular biology;
to train scientists, students and visitors at
all levels; to offer vital services to scientists
in the member states; to develop new instruments and methods in the life sciences and
to actively engage in technology transfer
activities. Around 190 students are enrolled
in EMBL’s International PhD programme. Additionally, the laboratory offers a platform
for dialogue with the general public through
various science communication activities such
as lecture series, visitor programmes and the
dissemination of scientific achievements.
Max Planck Institute for
Medical Research Heidelberg
The institute was founded in 1930 as the Kaiser
Wilhelm Institute for Medical Research, and
was re-founded as a Max Planck Institute in
1948. Its original goal was to apply the methods of physics and chemistry to basic medical
research, and it still works on fundamental biological questions that are of long-term medical
significance. One main area of research is
neurophysiology: What are the changes in
the brain that underlie processes like learning and remembering? What does the threedimensional circuit diagram of the billions
of nerve cells in the brain look like? How can
the processes in nerve cells in the living brain
be made visible through new microscopic
methods? A second main area of research at
the institute concerns the complex chemical
reactions in living cells. These are performed by
enzymes, and the research aims to determine
the atomic structure of important enzyme
molecules, particularly through the use of the
newly available free-electron lasers (FELs) in
difficult cases.
21
Core Facilities
22
CORE
FACILITIES
The DKFZ Core Facilities provide the infrastructure for
excellence. Cutting-edge techniques and equipment are
the foundation of high quality research.
At each core unit, experienced scientific and technical staff members assist researchers in the planning,
conduct and analysis of experiments. These services are
available to all DKFZ members and visiting scientists.
Research at DKFZ 2014
23
Core Facilities
Genomics and Proteomics
•
Next Generation Sequencing
Biomedical research increasingly depends on
global molecular analyses of normal and diseased phenotypes. These include qualitative as
well as quantitative investigations at the genome and proteome levels and are required to
eventually achieve a mechanistic understanding of disease or to identify novel markers
for diagnosis, prognosis or prediction. Central
infrastructures are key components in such
research processes, as these provide access to
state-of-the-art technology platforms that are
operated by dedicated personnel, thus overcoming redundant implementation of often
demanding technologies within an institute.
Accordingly, the Genomics and Proteomics
Core Facility (GPCF) at DKFZ covers four major
areas and provides professional services.
•
The genomics part of the facility operates one of Europe’s largest next-generation sequencing units and operates
•
within several national (e.g., DKTK) and
international (e.g., ICGC) cancer genome
projects, in addition to a variety of individual in-house projects. Gene expression
profiling, genotyping and methylation
analysis is carried out using array-based
technologies, providing high throughput
at reasonable cost. All these applications
generate molecular profiles at the level of
nucleic acids, providing information about
genetic as well as epigenetic alterations
in the disease context.
Technologies in mass spectrometry and
NMR are provided for qualitative and
quantitative analysis of proteins, protein
modifications and small molecules. These
applications allow views of the activation states of signaling proteins in cancer
pathways and help to generate mechanistic knowledge of tumor diseases. We
further provide small and large-scale
•
technologies to analyze protein-protein
interactions and interactions proteins
have with other molecules.
In the field of functional genomics, we
generate monoclonal antibodies targeting proteins as well as cancer-relevant
mutant variants. Some antibodies have
been licensed and are now used in diagnosis. Cell lines stably expressing recombinant proteins from isogenic loci in the
respective genomes are generated to assess phenotypes of proteins and mutants
in in vitro as well as in vivo systems, e.g.,
via generation of xenograft mouse models for the molecular characterization of
metastasis processes.
The central infrastructure of the GPCF offers assisted access to a number of costly
instruments being utilized by a number
of scientific groups, and it further distributes the human ORF clone resource of the
international ORFeome Collaboration for
recombinant expression of encoded proteins, also in isogenic cell lines.
Our mission is to enable the application of
state-of-the-art technologies. We carry out
joint projects with scientific groups within
DKFZ to implement the latest technologies
that serve science needs. In addition to providing full or assisted access to services, we are
involved in the DKFZ teaching program. Furthermore, the GPCF organizes tech-talks, seminars and practical courses where we inform
interested scientists, predocs and technicians
on the technological background of novel applications.
Head
PROF. DR. STEFAN WIEMANN
Units
Next Generation Sequencing
Microarray technologies
Bioinformatics (HUSAR)
Monoclonal Antibodies
Protein Analysis
Protein Interaction Screening
Molecular Structural Analysis
Isogenic Cell Line Technology
24
Core Facilities
Imaging and Cytometry
Biomedical research benefits greatly from
imaging and cell enrichment processes, but
scientific results in these fields are reliant upon
the efficient and correct use of complex and
expensive instrumentation. Dynamic progress
in the development of such technology results
in a constant requirement for new or updated
equipment, as well as experienced staff members able to guarantee the correct, appropriate
use of the instruments; execution of the experiments; and data management – all of which is
time consuming.
In order to minimize such investment of capital and personnel for individual groups, the
DKFZ has established the Imaging and Cytometry Core Facility; made up of individual units,
it provides a wide range of high quality services in four different fields for all DKFZ members
and visiting researchers.
Each unit is directed by a highly experienced
scientist. The units are responsible not only
for the allocation and maintenance of instruments, lab space and to some extent, consumables, but their scientific and technical staff
also offers training and assistance in sample
preparation, instrument application, experimental set-up design, interpretation of the results, and detailed, unit-specific seminars.
Small Animal Imaging
1.
2.
3.
Flow Cytometry
The Small Animal Imaging unit supports
clients with a variety of radiological methods, among them ultrasound, µPET, µCT,
µSPECT and MRT, to collect and quantify
morphological and functional data in vivo.
The Flow Cytometry unit performs cell
cloning or enrichment of up to 4 subpopulations simultaneously by using several
flow cytometric cell sorters (up to 5 laser,
cuvette and jet-in-air sorter), enabling
analysis of up to 19 parameters per cell.
The Light Microscopy unit provides a
number of manual and fully automated
wide-field and confocal laser-scanning
microscopes. The range of services is sup-
Light Microscopy
4.
Electron Microscopy
plemented by support in sample preparation (e.g. paraffin and cryo-sectioning,
laser microdissection) and spatial visualization of whole-mount specimens, as
well as data analysis and digital image
processing.
The Electron Microscopy (EM) unit offers full service and guided access in EM
preparation and imaging, including conventional Epon-EM, low-temperature EM
(high-pressure freezing, freeze substitution and cryo-sectioning), immuno-EM
and single particle EM (negative staining,
rotary shadowing).
Head
PROF. JÜRGEN KARTENBECK (IN CH.)
Units
Light Microscopy Facility
Core Facility Electron Microscopy
Small Animal Imaging
Flow Cytometry
Research at DKFZ 2014
25
Core Facilities
Information Technology
Information technology needs and requirements continue to increase at DKFZ. This is
due, in particular, to modern laboratory technologies in areas such as genome analysis and
radiological image processing, which generate
huge amounts of data on a petabyte scale.
Communication technology and office applications have penetrated our everyday work and
the introduction of the electronic laboratory
notebook has reinforced this trend. Furthermore, as more and more personal data are being processed, aspects of IT safety play an ever
more important role in many departments of
DKFZ and as a requirement in many national
and international scientific projects and collaborations such as the German Consortium
for Translational Cancer Research (DKTK). However, not only confidentiality and integrity of
data are important, the availability of IT is also
essential for scientific work. Therefore, redundant IT systems are needed in many places. IT
has gained a pivotal role as an enabling technology in the life sciences and particularly in
cancer research.
The task of the Information Technology Core
Facility (ITCF) is to optimize the use of information technology at DKFZ, to advise staff from
all in-house departments in selecting IT tools
for their specific needs in a general context, to
implement and operate centralized IT services
as well as to support the planning and operation of individual solutions. This is done on a
service-oriented basis. All essential strategic
and operative functions and tasks at DKFZ are
substantially supported by IT.
The Software Systems group provides central
IT software systems for both client and server
sides. These include, for example, central services such as user administration, software distribution and license monitoring, rights and resources management in file services, data base
servers, web servers, document management
and the electronic laboratory notebook.
The Databases group is responsible for database development and support for all in-house
departments. In addition, it provides technical
support for DKFZ’s Internet and Intranet presentations as well as survey tools and cooperation platforms.
The Desktop Services group runs the service
center for user inquiries, deals with all matters
related to the desktop environment such as
notebooks, MacOS, Windows and mobile devices, and runs the high-quality printing center.
Central servers, mail and file services, printing services, data storage as well as scientific
computing are the tasks of the Central Servers
group.
The Networks group takes care of the physical
data network, Internet connections, dedicated
connections to partners, and security services.
Head
HOLGER HAAS
Working Groups
Software Systems
Databases
Desktop Services
Central Servers
Networks
26
Core Facilities
Animal Laboratory Services
Cancer represents a devastating disease. The
mission of the DKFZ is research on the molecular mechanisms of carcinogenesis and the
improvement and development of cancer therapies. Scientists at the DKFZ work, whenever
possible, with cell cultures or try to answer
scientific questions by computer simulation
(replacement). In many cases, due to the complexity of tumorigenesis the significance of alternative in vitro or in silico systems is limited,
so that animal experiments are indispensable.
These are restricted to the minimum extent
possible (reduction); animals are treated with
respect and with the most advanced techniques (refinement). For their experiments,
DKFZ scientists preferentially use rodents, in
rare cases, amphibians also. To mimic the development of a distinct cancer in humans, cancer researchers employ various tumor models;
genetically manipulated mice with a tissuespecific gain or loss of one or several genes
serve to evaluate the functional role of such
genetic factors in cancer development.
To some extent, the mechanisms of tumor
development are analysed in mice that have
been treated with carcinogenic agents. To
study the characteristics of human tumor cells,
mice with a compromised immune system are
often used, since they tolerate the transplantation of cells from other species and allow their
growth.
The staff of the DKFZ Animal Laboratory Services Core Facility supports scientists requiring
animal organs or animals, bred in-house or
selectively purchased, for experimentation. A
team of clinical veterinarians and biologists
advises and assists researchers in the design
and realization of their experiments. Managers
of the core facility train technicians and caretakers and provide technical courses for scientific personnel. By these means, it is assured
that all animals are kept according to national
and international animal welfare laws. In addition, the welfare of the animals is ensured
by maintaining them under the most hygienic
conditions.
In the Laboratory of Microbiological Diagnostics and Animal Medicine, the health status of
the animals is regularly checked (www.dkfz.
de/en/abteilungen/v/v231.html). The Transgenic Service supports scientists at DKFZ in the
generation of genetically modified mouse lines
that serve for investigation of distinct human
tumor diseases (www.dkfz.de/en/transgenservice/index.html). In the Cryopreservation
Unit, the most important mouse strains are
preserved for further studies by collecting
spermatozoa or early-stage embryos from mutant mice and subsequent freezing in liquid
nitrogen. In addition, a database of all mouse
mutants available in-house is provided (www.
dkfz.de/en/kryokonservierung/index.html). The
Tumor Models Unit carries out cancer studies in
experimental animals by application of carcinogenic agents and by transplantation of tumor
cells into immune-deficient mice. Additionally,
diet and therapy studies are carried out (www.
dkfz.de/en/tumormodelle/index/html).
Head
PROF. DR. KURT REIFENBERG
Units
Tumor Models
Cryopreservation
Animal Laboratory Facility
Microbiological Diagnostic and
Laboratory Animal Medicine
Transgenic Service
Research at DKFZ 2014
27
Core Facilities
Library
amongst others, provided through the library’s
website. Currently, the library offers access
to more than 1000 e-journals. Monographs,
reference books, laboratory handbooks etc. are
available online, as well as in print. Publications that are not available from the library’s
collection may be ordered through document
delivery and thus made available.
Several databases are offered by the library
for literature searches. Here, the library offers
individually customized trainings in databases
like PubMed, Web of Science and SciFinder.
The same is true for the bibliographic management software EndNote and Reference
Manager.
The library’s reading room
The library’s reading room offers a quiet
working space with wireless internet and the
possibility of immediate help from the staff if
needed.
Due to technical development, research
and scientific communication processes are
currently facing large changes. Today, the
flood of information is rising rapidly. If this
information is used wisely in conjunction
with ever-increasing projects, tools and
programs, it will become a valuable addition
to researchers. Here, the library is supporting
the scientists in all aspects of “scientific
information and communication”.
The library’s team obtains the required
scientific literature and information which is,
We also offer assistance when questions involving bibliometric issues, citation analysis, open
access or copyright arise.
The library is also responsible for the DKFZ
publications database. Currently, the library is
working with scientists in order to expand the
database to an institutional repository.
Furthermore, the library is parenting the DKFZ
archive. This archive collects and registers all
documents regarding the history of the DKFZ.
Head
DAGMAR SITEK
28
Core Facilities
Joint Chemical Biology Core Facility of EMBL & DKFZ
Small inhibitory molecules are widely used as
therapeutic agents, but they are also excellent “bio-tool” compounds for basic research.
They are often used as experimental tools to
address important biological questions via
loss-of-function experiments. The aim of this
core facility is to provide research groups with
inhibitory molecules against their target of
interest and enable them to answer essential
questions in their research. The facility assists
groups in the development of primary and
secondary assays for screening against our
in-house compound library and guides them
through the process of identifying bio-tool
compounds for their specific target. It also offers computational chemistry services.
The Chemical Biology Core Facility is a collaboration between DKFZ, the European Molecular
Biology Laboratory (EMBL) in Heidelberg and
Heidelberg University, and is located at EMBL.
For further information on this service, please
visit the site: www.embl.de/services/core_facilities/chemcore/index.html
Medicinal chemistry support is usually
required following a small molecule screen.
Here, the research group “Cancer Drug Development” headed by Dr. Aubry Miller offers
assistance on a collaborative basis.
Ligand docked into target protein
Head
DR. JOE LEWIS
In cooperation with
EMBL
University of Heidelberg
Research at DKFZ 2014
29
30
Research Programs
RESEARCH
PROGRAMS
The DKFZ covers the entire breadth of modern cancer research.
Fields of research range from knowledge of the molecular basis of
the development of cancer, distribution and risk factors within the
population to diagnosis and treatment.
More than 100 division heads, group leaders and senior scientists,
200 postdocs and about 400 PhD students work together at the
DKFZ. As an interdisciplinary environment, DKFZ employs scientists
with qualifications in medicine, biology, biochemistry, physics, chemistry, mathematics, informatics or related issues.
At DKFZ, researchers benefit from intensive scientific exchange
between research programs and individual groups which serves as
a basis for the internationally renowned research at the center.
Research groups are organized in seven research programs: Cell
Biology and Tumor Biology, Functional and Structural Genomics,
Cancer Risk Factors and Prevention, Tumor Immunology, Imaging
and Radiooncology, Infection and Cancer, and Translational Cancer
Research.
Research at DKFZ 2014
31
Coordinator
PROF. DR. HELLMUT AUGUSTIN
Cell Biology and
Tumor Biology
Research Program (FSP-A) concentrates the basic cell and tumor biology-focused research
groups at the center. As such, the mission of the FSP-A groups is either the molecular,
cellular and functional analysis of the mechanisms leading to tumor initiation, tumor
promotion and tumor progression including metastasis or the pursuit of fundamental
discipline-independent basic science. Scientists of the research program “Cell and Tumor
Biology” aim at tackling these fundamental questions:
• They investigate how genome stability is ensured, as inherited or acquired alterations
in the genome are causative for tumor initiation and progression. The experimental
program also focuses on epigenetic mechanisms and RNA biology.
• They study cell surveillance and damage control mechanisms, which allow cells to
monitor molecular processes and respond to pathologic damage. This includes the
control of protein stability and turnover.
• They unravel critical signaling pathways and networks which enable cells to perceive
and correctly respond to information and to govern cellular processes. Scientists in
this research program investigate how dysregulation of these mechanisms is linked to
malignancies.
• They analyze cell differentiation pathways and the biology of stem and progenitor
cells taking into consideration that perturbed cell differentiation and dysregulated
stem cell programs are at the heart of many oncological and non-oncological diseases.
• They exploit the complexity of tumor cell interactions with their microenvironment to
analyze a tumor not just as a clump of tumor cells leading to local disease but rather
as a complex pathologic organ causing systemic disease. Metabolic changes are studied as risk factor and consequence of tumorigenesis and tumor progression.
To tackle these questions, the scientists employ a broad array of highly specialized molecular, cellular and organismic tools and techniques. With scientific excellence being the
primary recruitment criterion, outstanding groups are affiliated with the FSP-A. Thus, their
cutting-edge basic cell and tumor biology research establishes the knowledge-based
foundation for the rational translation and exploitation into medical application for some
of the most devastating human diseases. For a conceptually broader basic science appreciation beyond its primary tumor biology focus, DKFZ’s cell and tumor biology research
program is part of the DKFZ-ZMBH-Alliance, a strategic partnership between the FSP-A and
the Center for Molecular Biology of Heidelberg University (ZMBH) which was established
in 2007 in order to overcome the classical boundaries between the two strong university
and non-university institutions on the Heidelberg campus. Details about research projects
of the individual FSP-A research groups can be found on the respective pages.
32
Research Program
Genetically stably multicolor labelled
tumor cells for tumor cell heterogeneity
and biological competition experiments
Research at DKFZ 2014
33
Cell and Tumor Biology
Stem Cells and Cancer
Division
Head: Prof. Dr. Andreas Trumpp
Stem Cells and Cancer (A010)
Managing Director of the Heidelberg
Institute for Stem Cell Technology and
Experimental Medicine (HI-STEM gGmbH)
German Cancer Research Center
Im Neuenheimer Feld 280
69120 Heidelberg
Phone: +49 6221 42 3901
[email protected]
The adult bone marrow harbors a reservoir of
dormant HSCs. Although dormant HSCs do not
contribute to the day-to day generation of new
blood cells, they are efficiently and reversibly activated in response to bone marrow stress induced,
for example, by chemotherapeutic agents (5-FU)
or toxic substances (such as BrdU).
Stem cells are essential to maintain regenerative tissues and are critical components of repair in response to tissue injury and infection.
Moreover, genetic alterations of stem cells and
their progeny can lead to the generation of
“cancer stem cells” (CSCs) that drive tumorigenesis and metastasis in hierarchically organized cancer entities. Due to their remarkable
resistance to chemotherapy and radiation,
CSCs are thought to be responsible for tumor
re-occurrence and the initiation and maintenance of metastases.
One of the goals of our program is to elucidate
the molecular and cellular basis of hematopoietic stem cell (HSC) self-renewal and differentiation. We have recently shown that the most
potent HSCs during homeostasis are in a state
of deep dormancy. In response to stress signals
which can be mediated by bacterial (LPS) or
viral infections (Interferons) or by chemotherapy mediated cell loss, these dormant HSCs become activated to produce new stem cells and
progenitors (Figure). Using genome-wide transcriptomics, proteomics and methylome analysis (in collaboration with Prof. Christoph Plass),
we have recently established the molecular
landscape of HSCs and various progenitors in
the bone marrow to understand the molecular
basis of self-renewal and multipotency, as well
as the complex dynamic interactions between
stem cells and their niche.
In addition, the group has established a program to functionally characterize malignant
stem cells of leukemias and carcinomas at
various levels. For example, we have developed methods to isolate blood circulating
“metastasis initiating cells” (MICs) directly
from the peripheral blood of breast cancer
patients and characterized them function-
ally by transplanting them into immunocompromised mice. These studies revealed
the identification of MICs, which have an
EPCAM+CD44+MET+CD47+ phenotype and are
able to initiate new bone and lung metastasis. Moreover, the number of these MICs in the
blood of patients correlated with overall survival and offers novel possibilities for the design of better diagnostic and therapeutic tools
for metastatic breast cancer.
We have also identified novel subclasses of
pancreatic cancer and developed biomarkers to identify them. Stratification of patients
according to the subtypes revealed striking
differences in their overall survival and tumor
cells isolated from these patients show differential sensitivity to conventional and targeted
therapies. Next generation sequencing and
molecular characterization of subtype specific
cancer and metastasis stem cells will provide
the basis for the generation of novel diagnostic and therapeutic tools to target advanced
therapy resistant cancers including metastasis.
Future Outlook:
The “Stem Cells and Cancer” Division characterizes both normal and malignant stem cells
functionally using in vivo approaches. We then
use genomic, genetic, molecular and cellular
methods to uncover the mechanisms which
control and drive normal and uncontrolled
self-renewal. Starting with model systems, we
typically extend our work to the analysis of
primary patient derived samples (blood, bone
marrow, tumor samples, metastasis) with the
goal of developing innovative strategies to
detect and target cancer and metastasis stem
cells in clinical settings.
ESSENTIAL PUBLICATIONS:
(1.) Baccelli I. et al. (2013). Identification of a population of blood circulating tumor cells from breast cancer patients that initiates metastasis in a xenograft
assay. Nature Biotechnology, 31, 539–544.
(2.) Essers MAG. (2009). IFNa activates dormant HSCs
in vivo. Nature, 458, 904–908.
(3.) Wilson A. et al. (2008). Hematopoietic stem cells
reversibly switch from dormancy to self-renewal during homeostasis and repair. Cell, 135, 1118–1129.
(4.) Trumpp A. (2010). Awakening dormant haematopoietic stem cells. Nature Rev Immunol, 10, 201–209.
34
Research Program
Cell and Tumor Biology
Molecular Embryology
Division
Head: Prof. Dr. Christof Niehrs
Analyses of the molecular processes taking
place during embryonic development have
shown that the principles guiding embryonic
development in humans and in animals are
very similar on a molecular level. Today it is
known that genes involved in the development
also play a role in human diseases. The Division
of Molecular Embryology is studying mechanisms regulating cell differentiation. The aim
is to characterize molecular mechanisms
relevant for the formation of the body axis in
frogs and mice. To this end, we are identifying
developmental control genes and investigating
how these are regulated and what their functions are. Our special interest is investigating
the mechanisms of the Wnt signaling pathway
in this context.
Future Outlook:
Future research is aimed at identifying novel
Wnt pathway components, to study their role
and mechanism of action.
ESSENTIAL PUBLICATIONS:
(1.) Cruciat CM. et al. (2013). RNA helicase DDX3 is
a regulatory subunit of casein kinase 1 in Wnt-βcatenin signaling. Science, 339: 1436–1441.
(2.) Bilic J. et al. (2007). Wnt induces LRP6 signalosomes and promotes dishevelled-dependent LRP6
phosphorylation. Science, 316, 1619–1622.
(3.) Davidson G. et al. (2005). Casein kinase 1 couples
Wnt receptor signaling to the cytoplasmic transduction apparatus. Nature, 438, 867–872.
(4.) Glinka A. et al. (1998). Dickkopf-1 is a member of
a new family of secreted proteins and functions in
head induction. Nature, 391, 357–362.
Molecular Embryology (A050)
German Cancer Research Center
Im Neuenheimer Feld 280
69120 Heidelberg
Phone: +49 6221 42 4693
[email protected]
Two-headed Xenopus
embryo following
experimental
overstimulation of the
head inducer Dickkopf 1.
Research at DKFZ 2014
35
Cell and Tumor Biology
Signal Transduction and Growth Control
Divison
Head: Prof. Dr. Peter Angel
Signal Transduction and Growth Control (A100)
German Cancer Research Center
Im Neuenheimer Feld 280
69120 Heidelberg
Phone: +49 6221 42 4570
[email protected]
The Division is working on the characterisation
of the genetic response of organisms and their
cells to external signals (growth factors, inflammation-related cytokines, carcinogens and
tumor promoters) employing newly generated
genetically modified mouse models (which
replicate features of human diseases) and celland organ cultures derived thereof. We want
to define and characterize altered gene functions, which result in imbalanced signaling
pathways and downstream genetic programs
forming the basis for acquired capabilities of
uncontrolled cell growth, evasion of apoptosis,
sustained angiogenesis and finally enhanced
tissue invasion and metastasis. To date and
currently, we have applied genetically modified animal models, in vitro organ systems, and
genome-wide expression analyses in order to
decipher the individual functions of AP-1 subunits. Our study of individual AP-1 subunits, of
their regulation as well as the identification of
distinct targets genes and genetic programs
critically involved in cancer development and
progression has yielded major contributions
to our current understanding of genetic programs in physiological (e.g. embryogenesis,
vascular biology/angiogenesis, wound healing)
and pathological processes (chronic inflammation, tumorigenesis). In collaboration with
clinical partners these studies, accompanied
by analyses of human tumor samples, aim ultimately to define novel molecular markers for
diagnosis and therapeutic intervention.
state-of-the-art methods including modified
transgenic mice, various tumor models, interspecies heterologous co-culture cell systems,
genome-wide expression and epigenetic
analyses combined with systems biological
approaches, and molecular and cellular biology to study tumor-relevant genetic networks.
We will focus on mechanisms of cell-cell communication in wound healing, and cross-talk
between tumor cells and cells of the microenvironment (endothelial-, mesenchymal- and
immune cells). The main attention will be
focused on (soluble) mediators of cell communication as well as downstream signalling
pathways and genetic programs initiated in
the corresponding target cells.
The main projects concern:
1. Physiology and pathology of wound healing: controlling genetic programs of cell
proliferation, migration and differentiation.
2. Function of the cell surface protein podoplanin in brain and skin tumors.
3. Genetic and epigentic programs of tumor
angiogenesis and vessel physiology; role
of the tumor stroma.
4. Function of the cell surface receptor RAGE
and its ligands (S100 proteins) in the
regulation of genetic programs in inflammation and cancer.
ESSENTIAL PUBLICATIONS:
(1.) Szabowski A. et al. (2000). c-Jun and JunB antagonistically control cytokine-regulated mesenchymal-
Future Outlook:
With the goal to bridge basic science and
translational research, in collaboration with
partners at the DKFZ, University Heidelberg
and external partners, our program will focus
on intra- and intercellular signaling pathways
and downstream genetic programs in cancer
to develop and evaluate molecules as potential biomarkers or drug targets. We will utilize
epidermal interaction in skin. Cell 103, 745–755.
(2.) Hess J. et al. (2004). Functions of AP-1 subunits:
Quarrel and Harmony among Siblings. J. Cell Sci 117,
5965–5973.
(3.) Gebhardt C. et al. (2008) RAGE signaling sustains
inflammation and promotes tumor development;
J Exp Med 205, 275–285.
(4.) Licht A.H. et al. (2010). Junb regulates arterial contractility and cellular migration via its direct target
Myl9, J Clin Invest 120, 2307–2318.
36
Research Program
Immunohistological analysis of a mouse
liver tissue section showing induction of liver
progenitor cells (red) in response to chronic liver
damage in a murine model of inflammation
driven liver carcinogenesis.
Research at DKFZ 2014
37
Cell and Tumor Biology
Epigenetics
Division
Head: Prof. Dr. Frank Lyko
Epigenetics (A130)
German Cancer Research Center
Im Neuenheimer Feld 280
69120 Heidelberg
Phone: +49 6221 42 3800
[email protected]
Epigenetic mechanisms regulate the interpretation of genetic information and adapt gene
expression patterns to changing developmental or environmental contexts. Several epigenetic mechanisms have been identified so far,
with DNA cytosine methylation representing
the best-studied and possibly most relevant
epigenetic mark. Interestingly, cytosine methylation is also present in RNA, suggesting a
conserved epigenetic function of DNA and
RNA methylation. Our research focuses on understanding the biological function of cytosine
methylation as a versatile epigenetic mark.
Importantly, altered DNA methylation patterns
represent one of the earliest and most consistent hallmarks of human cancers. However,
the factors that shape the tumor methylome remain poorly understood. We are using
next-generation sequencing technologies to
analyze DNA methylation and hydroxymethylation patterns on the genome scale, with a
particular focus on mouse tumor models. We
have also established a novel research focus
on RNA methylation, which suggests that this
modification plays a key role in epigenetic regulation and inheritance. Finally, we are using
several unique model systems, such as honeybees, locusts and crayfish, to better understand
the role of epigenetics in ecological adaptation
and phenotypic plasticity.
Future Outlook:
The division will continue its focus on three
major topics: cancer epigenetics, RNA epigenetics and ecological epigenetics. To identify
the driving forces behind cancer-associated
epigenetic mutations, we will continue to develop our bioinformatics toolkit for the characterization of cancer epigenomes. To further
establish RNA methylation as a fundamentally
novel epigenetic mechanism, we will explore
the role of this modification in protein translation and small RNA silencing pathways. Finally,
we will further analyze the role of DNA methylation in ecological adaptation by establishing
marbled crayfish as a novel model system for
epigenetics research.
ESSENTIAL PUBLICATIONS:
(1.) Raddatz, G., et al. (2012). Dnmt3a protects active
chromosome domains against cancer-associated hypomethylation. PLoS Genetics, 8, e1003146.
(2.) Tuorto, F., et al. (2012). RNA cytosine methylation
by Dnmt2 and NSun2 promotes tRNA stability and
protein synthesis. Nature Structural and Molecular
Biology, 19, 900–905.
(3.) Lyko F. et al. (2010). The honey bee epigenomes:
differential methylation of brain DNA in queens and
Microscopic image
of cancer stem cells
expressing EGFP under
the control of the
OCT4-promoter.
38
Research Program
workers. PLoS Biology, 8, e1000506.
(4.) Schaefer M. et al. (2010). RNA methylation by Dnmt2 protects transfer RNAs against stress-induced
cleavage. Genes & Development, 24, 1590–1595.
Cell and Tumor Biology
DNA Repair Mechanisms and Cancer
Junior Research Group
Head: Dr. Hans Hombauer
The maintenance of the genome integrity
represents an important challenge for every
living organism. A variety of factors of environmental origin (chemicals, radiation, viruses,
etc), but also others intrinsic to the cellular
metabolism (i.e. oxidative species, DNA replication errors) are frequently damaging/altering
the information of the DNA.
Changes in the genetic information (mutations) are the cause of several human diseases,
including cancer. Not surprisingly, living organisms have developed a variety of DNA repair
mechanisms that in a concerted manner safeguard the stability of the genome.
Our research group investigates the molecular
mechanisms that allow DNA repair pathways
to preserve genome stability, specifically the
DNA mismatch repair (MMR) pathway. This
pathway is a post-replicative repair mechanism that increases DNA replication fidelity (to about three orders of magnitude) by
recognizing errors introduced during DNA
replication, and promoting repair by an excision and re-synthesis mechanism. Mutations
that inactivate MMR result in Lynch Syndrome,
also referred to as Hereditary Non-Polyposis
Colorectal Cancer (HNPCC). This syndrome is
characterized by genome instability, especially
at repetitive sequences or microsatellites (microsatellite instability or MSI) and early-onset
of colorectal and other types of cancer.
Furthermore, we are interested to identify and
characterize alternative mechanisms that can
result in MMR inactivation, and how specific
missense mutations inactivate MMR function
in a dominant manner. These studies might
reveal why specific MMR missense mutations
result in different degrees of cancer manifestation (i.e. early-onset, high penetrance, relapse).
Moreover, our future work aims at the identification and characterization of previously
unrecognized genes that affect DNA replication fidelity and repair. We expect that some
of these thus identified genes will at a future
date become essential diagnostic tools in cancer susceptibility syndromes.
ESSENTIAL PUBLICATIONS:
(1.) Hombauer H. et al. (2011). Visualization of Eukaryotic DNA Mismatch Repair Reveals Distinct Recog-
DNA Repair Mechanisms and Cancer (A310)
nition and Repair Associated Intermediates. Cell, 147,
German Cancer Research Center
1040–1053.
Im Neuenheimer Feld 581
(2.) Hombauer H., et al. (2011). Mismatch repair, but
not heteroduplex rejection, is temporally coupled to
69120 Heidelberg
replication in Saccharomyces cerevisiae. Science, 334,
Phone:+49 6221 42-3239
1713–1716.
[email protected]
(3.) Jaehnig E., et al. (2013). Checkpoint kinases regulate a global network of transcription factors in response to DNA damage. Cell Reports, 4, 174–188.
(4.) Smith C. et al. (2013). Dominant mutations in Saccharomyces cerevisiae PMS1 identify the Mlh1-Pms1
endonuclease active site and an Exonuclease 1-in-
Future Outlook:
We are interested in expanding the mechanistic understanding of the MMR reaction
by identifying and characterizing mutations/
genes that prevent the accumulation of mutations. To learn more about these processes, we
combine genetics, molecular and cell biology
approaches in S. cerevisiae and mammalian tissue culture.
Our studies aim to characterize the mechanistic aspects of the MMR reaction, in particular, the MMR repair intermediate Mlh1-Pms1
(Mlh1-Pms2 in humans), which we have recently identified as active sites of repair in budding yeast.
Research at DKFZ 2014
dependent mismatch repair pathway. PLoS Genetics, in press.
Visualization of
Mismatch repair Mlh1Pms1 complexes in
wild-type (A) and exo1Δ
mutant (B) in living
yeast cells. Deletion
of EXO1 results in
increased abundance of
Mlh1-Pms1 foci (some
foci examples are
indicated with white
arrows).
39
Cell and Tumor Biology
Redox Regulation
Division
Head: PD Dr. Tobias P. Dick
Redox Regulation (A160)
German Cancer Research Center
Im Neuenheimer Feld 280
69120 Heidelberg
Phone: +49 6221 42 2320
[email protected]
Elevated generation of oxidants (reactive oxygen species) is associated with inflammation
and many age-related disorders, including malignancy. Correspondingly, oxidants have been
generally regarded as unwanted and damaging products. However, more recently it has
become clear that some oxidants, in particular
hydrogen peroxide (H2O2), also play beneficial
roles as signaling molecules in healthy cells.
Oxidants regulate adaptive stress responses
and cell fate decisions through post-translational modification of transcription factors and
other target proteins. In particular, the signaling functions of oxidants are typically based
on the reversible oxidation of protein thiol
residues, leading to transient activation or inactivation of individual enzymes. In our laboratory we are investigating signaling pathways
by which H2O2 contributes to the regulation
of cellular physiology. We are interested in the
nature of redox alterations that accompany
chronic inflammation and malignant growth.
Special attention is devoted to the molecular
mechanisms by which oxidants achieve specificity as signaling molecules. Another area of
focus is to uncover the spatio-temporal dynamics of oxidative processes in vivo.
detailed understanding of these differences
may lead to new ideas as to how to interfere
with tumor growth.
Molecular mechanisms of oxidative signaling: How are H2O2-sensitive signaling proteins
oxidized in an efficient and specific manner?
Growing evidence suggests that certain peroxidases act as primary oxidant receptors and
pass on oxidizing equivalents to specific target
proteins.
Monitoring redox changes in cells, tissues and
organisms: We recently developed geneticallyencoded biosensors for oxidized glutathione
and H2O2. A major application is to monitor redox processes as they occur in the physiological context of the whole organism.
Fundamental principles of redox homeostasis:
The glutathione system is central to eukaryotic redox homeostasis and drug resistance
but remains incompletely understood. We are
combining redox imaging and reverse genetics
in the model eukaryote S. cerevisiae to reveal
the fundamental regulatory principles of the
glutathione system.
ESSENTIAL PUBLICATIONS:
(1.) Morgan, B. et al. (2013). Multiple glutathione di-
Future Outlook:
The role of H2O2 sensing and signaling in inflammation: H2O2 is released during tissue
injury and may act as one of the early signals
for the recruitment and activation of immune
cells. Recently, we identified H2O2-sensitive proteins involved in inflammatory signaling. Our
aim is to elucidate the specific links between
inflammatory activators, H2O2 and immune effector mechanisms.
Redox homeostasis in tumor cells: Many, if not
most, tumor cells differ in redox homeostasis
compared to their normal counterparts. More
Redox-sensitive cysteine residues (yellow)
can act as molecular switches.
40
Research Program
sulfide removal pathways mediate cytosolic redox
homeostasis. Nature Chemical Biology, 9, 119-125.
(2.) Albrecht S.C. et al. (2011). In vivo mapping of hydrogen peroxide and oxidized glutathione reveals
chemical and regional specificity of redox homeostasis. Cell Metab, 14, 819–829.
(3.) Gutscher M. et al. (2008). Real-time imaging of
the intracellular glutathione redox potential.
Nat Meth, 5, 553–559.
(4.) Kienast A. et al. (2007). Redox regulation of
peptide receptivity of major histocompatibility
complex class I molecules by ERp57 and tapasin. Nat Immunol, 8, 864–872.
Cell and Tumor Biology
Molecular Metabolic Control
Division
Head: Prof. Dr. Stephan Herzig
The department “Molecular Metabolic Control” is a common research unit between the
German Cancer Research Center (DKFZ), the
Center for Molecular Biology (ZMBH) at the
University of Heidelberg and the University
Hospital Heidelberg. The department is investigating the molecular basis of severe metabolic
disorders, including the Metabolic Syndrome
and type 2 diabetes, and their roles in tumor
initiation and progression. The main causes of
these metabolic disorders are believed to be
malfunctions in the activity of genes regulating our metabolism. By analyzing the signaldependent activity of such genes in response
to hormonal, nutritional and inflammatory
cues, we aim to define disease-causing malfunctions in glucose, fat and protein metabolism, ultimately aiming at the identification of
genes and gene products which increase the
susceptibility to metabolic diseases. Subsequently, identified gene defects are tested for
their potential to serve as molecular connections between metabolic and tumor diseases
and as potential novel drug targets within
these disease entities. Thus far, we have already characterized a number of molecular
switches that are dysregulated under certain
metabolic conditions and promote aberrant
metabolism in diabetes and cancer.
Future Outlook:
In the future, we will address the question if
and how the differential recruitment of specific transcriptional complexes to genomic target sites provides a molecular relay station for
nutritional, hormonal and inflammatory signals in the control of energy homeostasis and
the pathogenesis of aging-associated diseases,
including diabetes and cancer. Specifically, we
will investigate whether and how relevant
transcription factor complexes bridge metabolism, inflammation and tumor development
through the integrated control of metabolic
pathways, inflammatory responses, and cell
fate decisions.
By using a translational research approach,
we anticipate unravelling clinically significant
Research at DKFZ 2014
molecular determinants in the pathogenesis
of the Metabolic Syndrome and type 2 diabetes that are directly coupled to an increased
cancer risk in these patients, thereby serving as
potential new therapeutic targets in metabolic
disorders.
In particular, we will focus on three main areas
1. Transcriptional networks, systemic lipid
distribution, and lipotoxicity
2.Molecular integration of inflammation and
metabolism
3.Brown adipocyte stem cells and control of
energy homeostasis
ESSENTIAL PUBLICATIONS:
(1.) Kulozik Ph. et al. (2011). Hepatic deficiency in transcriptional co-factor TBL1 promotes liver steatosis
and hypertriglyceridemia. Cell Metabolism, 13, 389–
400.
(2.) Vegiopoulos A. et al. (2010). COX-2 controls ener-
Molecular Metabolic Control (A170)
gy homeostasis in mice by de novo recruitment of
German Cancer Research Center
brown adipocytes. Science, 328, 1158–1161.
Im Neuenheimer Feld 280
(3.) Lemke U. et al. (2008). The glucocorticoid receptor
controls hepatic dyslipidemia through Hes1. Cell Me-
69120 Heidelberg
tab., 8, 212–223.
Phone: +49 6221 42 3581
(4.) Herzig S. et al. (2001). CREB regulates hepatic glu-
[email protected]
coneogenesis through the coactivator PGC-1. Nature,
413, 179–183.
Lipid droplets (red)
in adipocytes serve
as main energy
supply for the body.
41
Cell and Tumor Biology
Vascular Oncology and Metastasis
Division
Head: Prof. Dr. Hellmut Augustin
Vascular Oncology and Metastasis (A190)
German Cancer Research Center
Im Neuenheimer Feld 280
69120 Heidelberg
Phone: +49 6221 42 1500
[email protected]
The Augustin laboratory studies the complexity of interactions occuring between tumor
cells and blood and lymphatic vessels during
tumor progression and metastasis, most notably as it relates to the growth of blood vessels in tumors. Angiogenesis, the sprouting of
new blood vessels from existing vessels, is an
oncofetal process that occurs physiologically
during development and postnatal growth,
but in adults is mostly restricted to pathological processes, which makes angiogenesis an
attractive target. Angiogenesis is characterized
by a distinct cascade of molecular and cellular
events, which enable cells of the vessel wall
(endothelial cells) to sprout from a pre-existing
capillary and to form new lumenized capillaries which anastomose to form a vascular
network that matures over time with the recruitment of perivascular mural cells (smooth
muscle cells, pericytes). Molecules of the
Angiopoietin/Tie ligand/receptor family play
central roles in these processes. Our scientists
study the molecular mechanisms of Angiopoietin/Tie signaling in blood and lymphatic vessels and analyze the molecular and functional
properties of endothelial cells and pericytes
during physiological and pathological angiogenesis and vessel remodeling. Given the critical roles of blood and lymphatic dysfunction
for numerous oncological and non-oncological
diseases, this work aimed at better understanding the complexity of vessel functions
has immediate translational implications for
subsequent therapeutic exploitation.
Future Outlook:
It is increasingly recognized that angiogenesisregulating molecules do not just control the
growth of blood and lymphatic vessels, but
also have critical maintenance functions in
the adult. Molecules of the Angiopoietin/Tie
ligand/receptor family exert gatekeeper functions within the vascular system to control
tissue homeostasis and serve metabolic maintenance functions. Future work of the laboratory will be aimed at better understanding the
molecular mechanisms of the vessel wall in
the control of tissue homeostasis, most notably as it relates to maintenance and repair processes. Experimental approaches include (i) the
vascular control of liver regeneration and liver
tumorigenesis, (ii) the role of blood vessels in
contributing to fibrotic tissue remodeling, (iii)
the role of the vasculature in controlling tissue metabolism, including obesity, (iv) the role
of blood vessels during ageing and the role of
vessel wall resident and bone marrow-derived
stem cells during this process, and (v) the role
of blood vessels in mediating the metastatic
dissemination of circulating tumor cells. The
lab will further intensify its efforts to elucidate
the molecular and functional properties of the
least well understood cells of the vessel wall,
the perivascular pericytes, a cell type lining
the outer surface of capillaries. We will study
pericyte-endothelial interactions in depth to
unravel pericyte function during pathological
conditions including fibrosis and tumor progression.
ESSENTIAL PUBLICATIONS:
(1.) Felcht M. et al. (2012). Angiopoietin-2 differentially regulates angiogenesis through Tie2 and integrin
signaling. J. Clin. Invest., 122, 1991–2005.
Mouse pups are born with an avascular retina.
After birth, retinal blood vessels grow centrifugally
from the optic disc over a period of 6 to 8 days to
form a complex sheet-like capillary network that
eventually prunes and matures over time. Due to
its versatility and opportunities for high resolution
analysis, the postnatal retinal angiogenesis model
has developed as the most popular model to study
angiogenesis in vivo.
(2.) Kutschera S. et al. (2011). Differential endothelial
transcriptomics identifies Semaphorin 3G as a vascular class 3 semaphorin. Arterioscler. Thromb. Vasc.
Biol., 31, 151–159.
(3.) Alajati A. et al. (2008). Spheroid-based engineering of a human vasculature in mice. Nature Methods,
5, 439–445.
(4.) Fiedler U. et al. (2006). Angiopoietin-2 sensitizes endothelial cells to TNF-alpha and has a crucial
role in the induction of inflammation. Nature Med.,
12, 235–239.
42
Research Program
Cell and Tumor Biology
Cell Growth and Proliferation
Division
Head: Prof. Dr. Bruce Edgar
The precise control of cell proliferation is essential for development in growing animals
and plants, and for tissue homeostasis in
adults. Loss of this control is a pre-requisite for
carcinogenesis. Research in Dr. Edgar’s group
focuses on the mechanisms that control cell
growth and proliferation using the Drosophila
model system. They use diverse molecular, genetic and cytological approaches to discover,
and then characterize, genes and pathways
that regulate the growth and proliferation of
cells in vivo in several different organs and tissue types in this small fruitfly. Genes discovered in this way often prove to be oncogenes
or tumor suppressors in humans, and thus
these basic studies fuel more applied cancer
research. Ongoing projects address the control
of cell proliferation by the E2F, Retinoblastoma, and APC/C complexes, the mechanism of
growth-dependent endoreplication cell cycles,
nutrient-regulated cell growth via the insulinTOR signaling network, and the regulation of
homeostatic and neoplastic growth in the fly’s
gut by intestinal stem cells.
Future Outlook:
The laboratory continues to focus on the regulation of the cell growth and proliferation in
several cell types in Drosophila. The main projects concern:
• Regulation of cell cycle exit during differentiation
• Cell cycle control by Hsp90 and the APC/C
ubiquitin ligase
• Control of Endocycles by E2F and the CRL4
ubiquitin ligase
• Growth regulation of the Endocycle
• Mechanism of endocycling in murine
trophoblast giant cells
Research at DKFZ 2014
•
•
•
•
Intestinal stem cell control by cell signaling pathways including Jak/Stat, EGFR/
Ras/MAPK, Hippo, and others
Whole-genome screens for regulators of
intestinal stem cell proliferation and differentiation
Cell cycle controls in intestinal stem cells
and their progeny
Development of an in vitro intestinal
stem cell culture model
ESSENTIAL PUBLICATIONS:
(1.) Jiang H. et al. (2009). Cytokine/Jak/Stat signaling
mediates regeneration and homeostasis in the Drosophila midgut. Cell, 137, 1343–1355.
(2.) Jiang H. et al. (2011). EGFR/Ras/MAPK signaling
mediates adult midgut epithelial homeostasis and
regeneration in Drosophila. Cell Stem Cell, 8, 84–95.
(3.) Shibutani S.T. et al. (2008). Intrinsic negative cell
Cell Growth and Proliferation (A220)
cycle regulation provided by PIP box- and Cul4Cdt2-
German Cancer Research Center
mediated destruction of E2f1 during S phase. Dev Cell,
ZMBH
15, 890–900.
Im Neuenheimer Feld 282
(4.) Shaw R.L. et al. (2010). The Hippo pathway regulates intestinal stem cell proliferation during Dros-
69120 Heidelberg
ophila adult midgut regeneration. Development, 137,
Phone: +49 6221 54 6827
4147–4158.
[email protected]
sSpi 24-96h AED!
Stem cell tumors (green cells) in a
fruit fly intestine caused by forced
activation of Spitz, a conserved EGFtype growth factor. The fly intestine
has many similarities to its human
counterpart, and is being used by
Dr. Edgar’s research group to
understand the genetic basis of
gastrointestinal tumorigenesis.
43
Cell and Tumor Biology
Clinical Neurobiology
Division in Cooperation with
Heidelberg University Medical Center
Head: Prof. Dr. Hannah Monyer
Clinical Neurobiology (A230)
German Cancer Research Center
Im Neuenheimer Feld 280
69120 Heidelberg
Phone: +49 6221 42 3100
[email protected]
The common theme of the lab projects regards
mechanisms underlying brain plasticity. One
effort is related to the differential contribution of distinct glutamate receptor subtypes
to short- and long-term synaptic plasticity and
the modulation of glutamate receptors by auxiliary proteins.
Furthermore we investigate the functional
role of GABAergic interneurons to learning and
memory. GABAergic interneurons are the principal source of inhibition in the adult brain and
synchronize the activity of neuronal networks
with millisecond precision, a prerequisite for
most higher brain functions. Projects focusing
on GABAergic interneuron function are tightly
interlinked and include studies at the molecular-cellular, network and behavioral level. We
identified molecular targets that are ideal to
manipulate GABAergic interneuron activity in
order to probe cell and network function. Thus,
we take recourse to genetically modified mice
with reduced GABAergic interneuron recruitment or altered connectivity and study the effect for spatial coding and memory. We focus
on the hippocampal-entorhinal formation,
a brain structure that is required for spatial
navigation in rodents and episodic memory in
humans. Finally, we study plasticity resulting
from the integration of newborn neurons into
established postnatal networks. Neurogenesis
projects focus on genes involved in cell generation, migration and differentiation.
2.
Projects revolving around GABAergic interneuron function will entail more local
genetic manipulation.
So far, the genetic manipulation affected
GABAergic interneurons in the whole forebrain
but it would be ideal to manipulate interneurons selectively in the hippocampal-entorhinal
cortex formation. Furthermore, virus-mediated
gene expression of light-activated channels
(e.g. Channelrhodopsin) allows the reliable
on-line identification of GABAergic interneurons in freely moving mice and subsequent
interference with the cellular activity during
behavioral performance. This approach opens
up possibilities to establish causal relationships between GABAergic interneuron activity,
spatial coding and memory. Finally, we discovered novel bidirectional GABAergic pathways
between hippocampus and medial entorhinal
cortex whose function for neuronal synchronization between these two major brain areas
remains to be established. 3) Projects regarding neurogenesis will focus on modification
of neurogenesis by environmental factors
and establish the functional significance of
neurogenesis for hippocampal and olfactory
learning.
ESSENTIAL PUBLICATIONS:
(1.) Melzer S. et al. (2012).Long-range-projecting
GABAergic neurons modulate inhibition in hippocampus and entorhinal cortex. Science. 335, 1506–
Future Outlook:
We will extend our ongoing investigations in
the following directions:
1. We will seek to unravel mechanisms by
which newly identified auxiliary proteins
modulate receptor signaling. We will determine interacting domains between
auxiliary proteins and receptors. Furthermore, we will establish whether the
expression of auxiliary proteins can be
modulated by activity.
1510.
(2.) Engelhardt J. et al. (2010). CKAMP44. A brain-specific protein attenuating short-term synaptic plasticity in the dentate gyrus. Science, 327, 1518–1522.
(3.) Korotkova T. et al. (2010). NMDA receptor ablation on parvalbumin-positive interneurons impairs
hippocampal synchrony, spatial representations, and
working memory. Neuron, 68, 557–569.
(4.) Allen K. et al. (2011). Gap junctions between interneurons are required for normal spatial coding in
the hippocampus and short-term spatial memory. J.
Neurosci., 31, 6542–6552.
44
Research Program
Cell and Tumor Biology
Chaperones and Proteases
Division
Head: Prof. Dr. Bernd Bukau
Our research aims at understanding the molecular basis of the intricate functional network of chaperones and proteases responsible
for maintaining protein homeostasis in the
cytosol. Our main focus is on:
(1) Biogenesis of proteins. Concurrently with
their synthesis, nascent polypeptides are subjected to enzymatic processing, chaperoneassisted folding or membrane targeting, processes for which the ribosome serves as docking platform of enzymes, targeting factors and
chaperones. We are dissecting these events
and the relationship between translation and
protein folding/assembly.
(2) Functional network of Hsp70 chaperone
machines. The Hsp70 chaperone network constitutes a versatile cellular system regulating
protein conformation. We analyze the mechanism of Hsp70 and co-chaperones in protein
quality control.
(3) Cellular strategies coping with protein
misfolding and aggregation. Protein aggregation is an organised process in vivo, leading to
deposition of aggregates at specific cellular
sites. We are determining parameters and factors controlling protein aggregation, and are
dissecting the mechanism of clearance of misfolded and aggregated proteins by chaperones
and proteases.
2.
3.
Functional network of Hsp70 chaperone
machines. How do J-proteins activate
the Hsp70 cycle? How do nucleotide exchange factors of the Hsp110 family cooperate with Hsp70 in protein quality control? How do Hsp70-J-proteins distinguish
the different categories of client proteins?
Cellular strategies coping with protein
misfolding and aggregation. What mechanisms mediate sorting of aggregationprone proteins into distinct deposits?
Which factors are responsible for clearance of misfolded/aggregated proteins?
How do AAA+ chaperones and Hsp70 systems mediate protein disaggregation and
refolding? What is the basis for the triage
decision between degradation and refolding of misfolded proteins?
ESSENTIAL PUBLICATIONS:
(1.) Oh E. et al. (2011). Selective ribosome profiling re-
Chaperones and Proteases (A250)
German Cancer Research Center
ZMBH
Im Neuenheimer Feld 282
69120 Heidelberg
Phone: +49 6221 54 6795
[email protected]
veals the cotranslational chaperone action of trigger
factor in vivo. Cell 147, 1295–1308.
(2.) Erbse A. et al. (2006). ClpS is an essential component of the N-end rule pathway in Escherichia coli.
Nature. 439, 753–756.
(3.) Weibezahn J. et al. (2004). Thermotolerance requires refolding of aggregated proteins by substrate
translocation through the central pore of ClpB. Cell,
119, 653–665.
Future Outlook:
We will focus on three long-term topics:
1. Biogenesis of proteins. What are the
mechanisms of chaperone-assisted cotranslational protein folding? What is
the basis for functional orchestration
of ribosome-associated chaperones, enzymes and targeting factors? Is protein
assembly a co-translational process, in
which nascent chains of components of a
protein complex interact with other complex components to achieve assembly.
Does the translation process itself control
protein assembly?
Research at DKFZ 2014
(4.) Tyedmers J. et al. (2010). Cellular strategies for
controlling protein aggregation. Nat. Rev. Cell Biol.
11, 777–788.
Mechanism of protein aggregate
dissolution through Hsp70/Hsp100
cooperation. The ring-shaped Hsp100 has
two structural states, one inactive and the
other activated. A molecular toggle keeps
the Hsp100 chaperone in the inactive
state. Hsp70 causes the toggle to flip,
thereby activating the Hsp100 chaperone.
In this state it can pull protein strands out
of the aggregate. The activation of Hsp100
is not permanent, with the chaperone
reverting to the repressed state after the
aggregate has dissolved.
Hsp100
Hsp100
inactive
activated
Hsp70
protein aggregate
45
Cell and Tumor Biology
Molecular Neurobiology
Division
Head: Prof. Dr. Ana Martin-Villalba
Molecular Neurobiology (A290)
German Cancer Research Center
Im Neuenheimer Feld 280
69120 Heidelberg
Unraveling the complex functions of CD95 in
the central nervous system has been the main
focus of our research in the past years. In particular, we discovered the multiple roles played
by CD95 in different neural, immune and tumor cells. We have identified the CD95 as a
major trigger of cell migration/invasion leading to recruitment of inflammatory cells and
tumor progression. On the other hand, CD95
crucially contributes to stem cell survival and
lineage differentiation. Our current research
focus is on further characterization of stem cell
biology in homeostasis and response to injury
in the brain and pancreas; the role of inflammation in neurodegenerative diseases such as
Parkinson disease and autoimmune diseases;
and the role of stem cells and inflammation in
glioblastoma- and pancreatic adenocarcinoma-initiation and progression. To tackle these
questions, we combine biochemical and modern genomic technologies as well as cell biology and genetics in human cells and mouse
model systems.
Future Outlook:
Stem cells in adulthood are involved in tissue
homeostasis and response to injury. Alteration
of the default program controlling stem cell‘s
proliferation, survival and differentiation in
these scenarios set the ground for tumor initiation. Our current and future research centers on understanding the molecular program
involved in the control of stem cell quiescence/
activation in the brain and pancreas during
homeostasis and disease and its modulation
by the innate immune system. Findings from
adult stem cells will be further examined in
human cancer stem cells and animal models of
glioblastoma and pancreatic adenocarcinoma.
Our research intends to contribute to the identification of molecular mechanisms involved in
stem cells’ biology, and tumor initiation and/or
progression.
ESSENTIAL PUBLICATIONS:
(1.) Letellier E. et al. (2010). CD95-ligand on peripheral myeloid cells activates Syk kinase to trigger their
recruitment to the inflammatory site. Immunity, 32,
Phone: +49 6221 42 3766
240–252. This article was picked and evaluated by
“Faculty of 1000” with a F1000 Factor of 6 http://
[email protected]
f1000biology.com/article/id/2629957.
(2.) Corsini N. et al. (2009). The death receptor CD95
activates adult neural stem cells for working memory
formation and brain repair. Cell Stem Cell, 5, 178–190.
(3.) Kleber S. et al. (2008). Yes and PI3K bind CD95 to
signal invasion of glioblastoma. Cancer Cell, 13, 235–
248. This article was picked and evaluated by “Faculty
of 1000” members with a F1000 Factor of 3.2.http://
f1000medicine.com/article/id/1119774/evaluation.
(4.) Sancho-Martinez I. et al. (2009). Tyrosine phosphorylation and CD95: a FAScinating switch. Cell Cycle 8, 838–842.
Neurosphere derived from neural stem cells
from the subventricular zone of NestinCre-ERT2 iYFP reporter mice 24 hours after
tamoxifen induction.
46
Research Program
Cell and Tumor Biology
Molecular Biology of the Cell II
Division
Head: Prof. Dr. Ingrid Grummt
Our group identifies, characterizes and exploits
the molecular mechanisms that control gene
expression at the genetic and epigenetic level,
aiming to understand the chain of events by
which external signals are transferred into
the cell nucleus to regulate transcription of
specific genes. Focussing on the role of nuclear
noncoding RNA (ncRNA) in chromatin structure and epigenetic regulation, we found that
ncRNA has an impact on many chromatinmediated processes, linking both RNA and chromatin fields. We have discovered a novel RNAbased strategy for epigenetic programming,
showing that ncRNAs are capable of forming
DNA:RNA triplexes with regulatory gene sequences. These triplex structures are specifically recognized by the DNA methyltransferase
DNMT3b, thereby inducing DNA methylation
and transcriptional silencing. Other ncRNAs
guide histone modifying enzymes to specific
genomic sites, demonstrating that ncRNAs can
act as selective ligands for chromatin modifying enzymes. Deciphering novel epigenetic and
metabolic control mechanisms of gene expression will reveal how epigenetic defects cause
human diseases and will be instrumental in
facilitating therapeutic strategies in the future.
regulation of chromatin and transcription and
will investigate the mechanism by which these
ncRNAs regulate the function of transcription
factors and chromatin modifying enzymes. We
will perform genome-wide analyses to explore
with which proteins these regulatory RNAs
are associated and will validate their role in
key biological processes. We expect that in the
long term, these studies will lead to an understanding of the mechanisms that propagate
a specific chromatin structure through cell
division and will provide mechanistic insights
into the functions of ncRNAs in transcriptional
regulation.
ESSENTIAL PUBLICATIONS:
(1.) Schmitz K.-M. et al. (2010). Triplex formation between noncoding RNA and DNA targets DNMT3b to
regulatory gene regions. Genes&Dev. 24, 2265–2269.
(2.) Feng W. et al. (2010). PHF8 activitates transcrip-
Molecular Biology of the Cell II (A030)
tion of rRNA genes through H3K4me3 binding and
German Cancer Research Center
H3K9me1/2 demethylation. Nature Struct. Mol. Biol.
Im Neuenheimer Feld 581
17, 445–450.
(3.) Zhou Y. et al. (2009). Acetylation by hMOF regu-
69120 Heidelberg
lates NoRC-dependent heterochromatin formation,
Phone: +49 6221 42 3423
nucleosome positioning and transcriptional silenc-
[email protected]
ing. Nature Cell Biol. 11, 1010–1016.
(4.) Mayer C. et al. (2006). Intergenic transcripts regu-
Future Outlook:
Evidence from a variety of experimental systems demonstrates that non-coding RNAs
(ncRNAs) play a significant role in the control
of gene expression and epigenetic regulation. It seems that ncRNAs are numerous and
highly adapted in roles that require specific
nucleic acid recognition without complex catalysis, such as in guiding RNA modifications
or in directing post-transcriptional regulation
of gene expression and chromatin structure.
We intend to identify ncRNAs involved in the
Research at DKFZ 2014
late the epigenetic state of rRNA genes. Mol. Cell
22, 351–361.
Non-coding RNAs
act in concert with
chromatin modifying
enzymes to establish
distinct epigenetic marks
at transcriptionally
active and silent genes,
characterized by specific
nucleosome positions,
histone marks (Ac, Me),
and DNA methylation
(CH3).
47
Cell and Tumor Biology
Cell Biology
Helmholtz Professorship
Head: Prof. Dr. Werner W. Franke
Cell Biology (A991)
German Cancer Research Center
Im Neuenheimer Feld 280
69120 Heidelberg
Phone: +49 6221 42 3212
[email protected]
Cell morphology, character, function and interaction with other cells are established and
predominantly determined by their architectonic organization, i.e. the cytoskeleton, in both
normal and pathological states, in situ and in
cell culture. In particular, our studies focus on
the structural and molecular elements forming the cytoplasmic filament systems, notably
the microfilament bundles as well as the intermediate-sized filaments and their anchorage
structures, the dense plaques located on the
cytoplasmic sides of the cell-cell connecting
junctions, i.e. primarily the adhering junctions
and the desmosomes. We are extending and
completing our analyses of the major constituent molecules of these cell type-specific junctions using biochemical and immunological
methods, including chemical cross-linking as
well as high-resolution immunofluorescence
and immunoelectron microscopy. To this end,
we generate antibodies against cell typespecific cytoskeletal molecules and examine,
in collaboration with pathologists, their diagnostic value for tumor cell typing, notably for
the identification of the specific primary tumor
of metastatic tumor cells. In addition, we have
recently demonstrated spontaneous and cumulative syntheses of proteins that then can
be assembled to certain novel and semistable
structures, including cell-cell junctions, that
are able to transform “out of histogenesis” a
given tumor cell type directly to a novel different tumor cell type.
Double-label immunofluorescence
microscopy of a monolayer culture of
epithelial cells (human keratinocytes of line
HaCaT) connected by cell-cell bridges with
central desmosomes (red and yellow show
the major molecule, desmoplakin) anchoring
bundles of keratin filaments (green). For
details see W.W. Franke (2009) Cold Spring
Harb. Perspect. Biol. 1, a003061.
48
Research Program
Future Outlook:
The ongoing and future work aims at the
completion of the molecular composition of
the cell-cell junctions and the identification
of novel types of junctions; their specific functions and mode of formation; the elucidation
of their value in tumor diagnosis; and of their
roles in tumor spread and metastasis.
ESSENTIAL PUBLICATIONS:
(1.) Franke W.W. et al. (2013). Transmembrane protein
PERP is a component of tessellate junctions and of
other junctional and non-junctional plasma membrane regions in diverse epitheliail and epitheliumderived cells. Cell Tissue Res. 353, 99–115.
(2.) Franke W.W. & Pape U.-F. (2012). Diverse types of
junctions containing tight junction proteins in stratifi ed mammalian epithelia. Ann. N. Y. Acad. Sci., 1257,
152–157.
(3.) Pieperhoff S. et al. (2012). The plaque protein myozap identified as a novel major component of adhering junctions in endothelia of the blood and lymph
vascular systems. J. Cell. Mol. Med., 16, 1709–1719.
(4.) Franke W.W. & Rickelt S. (2011). Mesenchymal-epithelial transitions: Spontaneous and cumulative syntheses of epithelial marker molecules and their assemblies to novel cell junctions connecting human
hematopoietic tumor cells to carcinomatoid tissue
structures. Int. J. Cancer, 129, 2588–2599.
Cell and Tumor Biology
Molecular Biology of the Cell I
Helmholtz Professorship
Head: Prof. Dr. Günther Schütz
Our laboratory is studying the role of nuclear
receptors during normal development and disease. Since germline-inactivation of the mineralocorticoid receptor (MR) or the glucocorticoid
receptor (GR) gene results in early lethality, we
generated mutant mice with neuron-specifc
inactivation of either gene in the forebrain.
To avoid effects on brain development, we established a transgenic mouse line that allows
inducible gene inactivation in adult forebrain
neurons.
The subventricular zone (SVZ) of the lateral
ventricle and the subgranular zone (SGZ) of
the dentate gyrus (DG) are the largest germinal zones of sustained neurogenesis during
adulthood. We found that the orphan nuclear
receptor tailless (Tlx) is exclusively expressed
in these slowly dividing neural stem cells
(NSCs). We also found that overexpression of
Tlx induced expansion of the neural stem cell
population in mice. These cells initiate the development of glioma-like lesions and gliomas.
Glioma development is accelerated upon loss
of the tumor suppressor p53 in adult neural
stem cells. Therefore, our goal is to generate
transgenic mouse models that will allow for
elucidation of the molecular mechanisms involved in disease development.
In a novel project we study the function of
microRNAs in adult neural stem cells and
neurons, their impact on neural plasticity, and
their involvement in the CNS control of energy
balance and metabolism.
Future Outlook:
The major aims in our future work will be:
genome-wide identification of binding sites of
the mineralo- and glucocorticoid receptor in
the hippocampus by ChIP-Seq methodology.
With this method we will identify the regulatory sequences that cause spatial and temporal expression of the target genes of these nuclear receptors. We anticipate that with these
approaches, chromatin immunoprecipitation
coupled to massively parallel sequencing, the
characterization of target genes for these
nuclear receptors (GR, MR) will be possible.
These efforts will thus lead to a molecular understanding of the action of these regulatory
factors.
Molecular Biology of the Cell I (A992)
ESSENTIAL PUBLICATIONS:
(1.)Kirilov, M. et al. (2013). Dependence of fertility on
German Cancer Research Center
kisspeptin-Gpr54-signaling at the GnRH neuron.
Im Neuenheimer Feld 280
Nat. Commun., 4, 2492. doi: 10.1038/ncomms3492.
69120 Heidelberg
(2.) Habermehl D. et al. (2011). Glucocorticoid activity
Phone: +49 6221 42 3411
during lung maturation is essential in mesenchymal
[email protected]
and less in alveolar epithelial cells. Mol. Endocrinol.,
25, 1280–1288.
(3.) Liu H.-K. et al. (2010). The nuclear receptor tailless
induces long term neural stem cell expansion and
brain tumor initiation. Genes. Dev., 24, 683–695.
(4.) Engblom D. et al. (2008). Glutamate receptors
on dopamine neurons control the persistence of cocaine-seeking. Neuron, 59, 497–508.
glucocorticoids
GR
+
GRE
-
+
AP1 or NFкB
The glucocorticoid receptor
modulates transcription by
different modes of action.
Research at DKFZ 2014
P
STAT5
STAT5
P
nGRE
49
Cell and Tumor Biology
Molecular Biology of Centrosomes and Cilia
Helmholtz University Junior Research Group
Head: Dr. Gislene Pereira
Molecular Biology of Centrosomes and Cilia
(A180)
German Cancer Research Center
Im Neuenheimer Feld 581
69120 Heidelberg
Phone: +49 6221 42 3447
[email protected]
Centrosomes of mammalian and fungi cells
play a decisive role in the temporal and spatial organisation of the microtubules of the
bipolar spindle, which segregates the sister
chromatids to opposite poles of the cell during
mitosis. In addition, a large body of evidence
suggests that centrosomes also function as a
signalling platform that integrates a multitude
of cellular signals to control cell fate determination and/or cell cycle progression. Our lab
has a long-standing interest in understanding
how centrosome-associated components control mitotic exit and cytokinesis on a molecular
level. Our work has significantly contributed to
the identification and molecular characterisation of a centrosome-associated mitotic checkpoint, named as the spindle position checkpoint (SPOC). This checkpoint stops cell cycle
progression in response to mis-orientation of
the mitotic spindle along the mother-daughter
cell polarity axis. More recently, a similar centrosome-based SPOC mechanism was reported
to exist in higher eukaryotic cells undergoing asymmetric cell divisions. This highlights
an important functional conservation, which
is currently being explored by our group. In
addition, we are investigating the molecular
mechanisms by which two conserved centrosome-associated cell cycle regulators, the NDR
kinase Dbf2 and the phosphatase Cdc14, regulate cytokinesis (i.e. the physical separation of
mother and daughter cells) after completion
of mitosis.
Future Outlook:
In all eukaryotic cells, mitotic checkpoints and
the temporal and spatial control of cytokinesis
are of extreme importance for the maintenance and the accurate segregation of the
genome. Therefore, the molecular characterisation of SPOC signalling and cell cycle control
of cytokinesis will constitute an important
part of our future research. In addition, over
the last five years, we became interested in
investigating how specialised sub-structures
of centrosomes, named centrioles, serve as a
template for the formation of the basal body,
from which cilia and flagella are assembled.
Cilia are highly conserved microtubule-based
organelles that play an essential role in signalling and cell motility. Defects in the formation or function of cilia are related to a large
number of severe genetic disorders, known as
ciliopathies. Our aims are to understand the
molecular mechanisms that control the transition from centriole to basal body and how ciliogenesis is coordinated with cell cycle progression in mammalian cells.
For more information about our research
activities, please visit our website:
www.dkfz.de/en/celldivision/index.php
ESSENTIAL PUBLICATIONS:
(1.) Caydasi A.K. et al. (2009). Spindle alignment regulates the dynamic association of checkpoint proteins
with yeast spindle pole bodies. Dev Cell., 16, 146–156.
Cell division imaged
in the budding yeast
Saccharomyces
cerevisiae. The
chromosomes are
shown in blue, the
mitotic spindle
in green and the
centrosome.
(2.) Meitinger F. et al. (2011). Phosphorylation-dependent regulation of the F-BAR protein Hof1 during cytokinesis. Genes & Dev., 25, 875–888.
(3.) Schmidt K.N. et al. (2012). Cep164 mediates vesicular docking to the mother centriole during early steps
of ciliogenesis, J. Cell Biol., 199, 1083–1101.
(4.) Kuhns S. et al. (2013). The microtubule affinity regulating kinase MARK4 promotes axoneme extension
during early ciliogenesis. J. Cell Biol., 200, 505–522.
50
Research Program
Cell and Tumor Biology
Posttranscriptional Control of Gene Expression
Helmholtz University Junior Research Group
Head: PD Dr. Georg Stöcklin
In eukaryotes, the activity of all genes depends
on the level of transcription in the nucleus.
In
addition, many genes are regulated at the
post-transcriptional level by mechanisms that
control the translation efficiency and degradation rate of individual mRNAs in the cytoplasm.
This allows cells to respond rapidly to external
stimuli and alter protein expression levels
directly. Our lab examines control of translation and mRNA decay in human cell lines and
mouse macrophages. We have extensively analyzed a group of unstable mRNAs that contain
adenylate-urylate(AU)-rich elements and the
cognate RNA-binding proteins that regulate
the stability of these mRNAs. More recently,
we identified a novel class of stem-loop motifs,
which promote mRNA degradation by recruiting a protein termed Roquin. Importantly, this
stem-loop motif is present in the mRNA encoding TNF, the most potent pro-inflammatory
cytokine of the mammalian organism.
Through a transcriptome-wide analysis, we
identified a distinct group of mRNAs whose
translation is specifically regulated during the
course of macrophage activation. Interestingly,
we found that many feedback inhibitors of the
NF-kB pathway are regulated at the level of
translation; current experiments address the
molecular mechanisms underlying this mode
of regulation.
Cells exposed to environmental stress respond
by reducing their global rate of translation. We
discovered that translation suppression in response to cold shock is mediated via an unusual pathway and is essential for cells to survive
hypothermia, underlying the importance of
posttranscriptional control mechanisms. Currently, we are investigating the mechanisms by
which hypoxia and oxidative stress suppress
global protein synthesis.
Finally, we discovered an RNA-binding protein
that is required for cell cycle arrest after DNA
damage. Loss of this protein causes mitotic errors and the accumulation of damaged DNA.
Importantly, reduced expression of this protein
in human squamous cell carcinoma also correlates with reduced patient survival. Our current
Research at DKFZ 2014
efforts are to determine the molecular mechanism by which this RNA-binding protein exerts
its function in the DNA damage response.
Future Outlook:
Future work in the lab will focus on identifying novel cis-acting elements and trans-acting
factors that control both the degradation and
translation of specifically regulated mRNAs. In
addition, we examine the mechanisms responsible for suppressing global protein synthesis
in response to environmental stress signals.
ESSENTIAL PUBLICATIONS:
(1.) Leppek K. et al. (2013). Roquin promotes constitutive mRNA decay via a conserved class of stem-loop
recognition motifs. Cell, 153, 869–881.
(2.) Hofmann S. et al. (2012). Translation suppression
promotes stress granule formation and cell survival in response to cold shock. Mol Biol Cell., 23, 3786–
Posttranscriptional Control of Gene Expression
(A200)
German Cancer Research Center
3800.
Im Neuenheimer Feld 280
(3.) Spasic M. et al. (2012). Genome-wide assessment
69120 Heidelberg
of AU-rich elements by the AREScore algorithm. PLoS
Phone +49 6221 54 6887
Genet., 8(1):e1002433. doi: 10.1371/journal.
(4.) Sandler H. et al. (2011). Not1 mediates recruitment of the deadenylase Caf1 to mRNAs targeted for
degradation by tristetraprolin. Nucleic Acids Res., 39,
[email protected]
and Zentrum für Molekulare Biologie der
Universität Heidelberg (ZMBH)
4373–4386.
During cold shock,
mammalian cells suppress
protein synthesis.
Translationally arrested
mRNAs assemble into
stress granules (cyan) in
the cytoplasm and the
mitochondrial network
(green) shows severe
alterations. Nuclei are
visualized in purple.
51
Cell and Tumor Biology
Cellular Senescence
Junior Research Group
Head: Dr. Thomas G. Hofmann
Cellular Senescence (A210)
German Cancer Research Center
Im Neuenheimer Feld 280
69120 Heidelberg
Phone: +49 6221 42 4631
[email protected]
The DNA damage response (DDR) is at the
heart of cancer etiology. Cancer cells show a
dysfunctional DDR which is associated with
increased genomic instability and resistance
to DNA damage-inducing treatments. Cells respond to DNA damage by tipping the cell fate
balance to achieve one of the following outcomes: DNA repair, cellular senescence, or cell
death. Commitment to a particular cell fate is
regulated by an evolutionary conserved signal
transduction network which is coordinated by
a set of DNA damage-responsive checkpoint
kinases. Our research group is studying the
regulatory processes controlling cell fate decisions in response to DNA damage. Our aim is
to elucidate the molecular mechanisms underlying the selectivity of the cellular decision
process in response to damage insults, which
could vary between DNA repair, cell death, and
senescence. To this end, we are identifying
novel regulators and substrates of checkpoint
kinases, and investigating their biological function and mechanism of action in the DDR network. We have a particular interest in understanding the function of proteins localizing to
specific nuclear domains termed Promyelocytic leukemia (PML) bodies. Indeed, PML bodies
have been proposed to act as nuclear cell fate
regulatory centers.
Future Outlook:
Our goal is to yield sufficient insight into cell
fate control mechanisms in order to define
molecular targets which will allow us to modulate the DDR in cancer cells, and subsequently
channel it towards cell elimination.
ESSENTIAL PUBLICATIONS:
(1.) Bitomsky N. et al. (2013). Autophosphorylation and
Pin1 binding coordinate DNA damage-induced HIPK2
activation and cell death. Proc. Natl. Acad. Sci. USA,
(epub ahead of print).
(2.) Winter M. et al. (2008). Control of tumor suppressor HIPK2 stability by ubiquitin ligase Siah-1 and
checkpoint kinases ATM and ATR. Nature Cell
Biology, 10, 812–824.
(3.) Milovic-Holm K. et al. (2007). FLASH links the
CD95 signaling pathway to the cell nucleus and nuclear bodies. EMBO J., 26, 391–401.
(4.) Hofmann T.G. et al. (2002). Regulation of p53 activity by its interaction with Homeodomain-interacting protein kinase-2. Nature Cell Biology, 4, 1–10.
DNA damage checkpoint kinases (red & green)
are recruited to DNA double-strand breaks at
chromatin (blue) following ionizing radiation.
52
Research Program
Cell and Tumor Biology
Normal and Neoplastic CNS Stem Cells
Junior Research Group
Head: Dr. Hai-Kun Liu
Active adult neurogenesis is one of the most
exciting discoveries in neuroscience of the
last decade. The subventricular zone (SVZ) of
the lateral ventricle (LV) and the subgranular
zone (SGZ) of the dentate gyrus (DG) in the
hippocampus are the largest germinal zones
of sustained neurogenesis during adulthood
in the mammalian central nervous system.
Astrocyte-like type B cells in the adult SVZ are
thought to be multipotent neural stem cells
(NSCs). These cells give rise to transient amplifying type C cells, which in turn differentiate
into type A cells (neuroblasts) that migrate to
the olfactory bulb (OB) through the rostral migratory stream (RMS). NSCs in the SGZ mainly
give rise to new granular cells in the DG which
are thought to be important for spatial learning and memory. Adult neurogenesis in the
SVZ represents a unique system to study regulation of NSC proliferation, differentiation and
directed neuronal migration in vivo. Strikingly,
these cells can also initiate gliomagenesis after acquiring the same oncogenic mutations
which were found in human brain tumor patients. Our lab aims to identify crucial molecular pathways that are important for the regulation of normal and neoplastic neural stem
cells. To achieve this goal, we are mainly using
mouse models in which we have altered the
activity of some oncogenes, tumor suppressors
and chromatin remodellers specifically in adult
mouse neural stem cells.
2.
3.
tity of stem cells and their progenies.
One of the major focuses in our lab is to
understand the interplay between crucial transcriptional factor and chromatin
remodelers, in particular their functions
during neural stem cell self-renewal and
differentiation.
Neoplastic neural stem cells:
One important issue of targeting braintumor stem cells (BTSCs) is to avoid damaging normal stem cells. Thus our goal is
to identify critical differences between
normal and tumor stem cells which will
provide important information for targeting exclusively BTSCs.
Mouse models of brain tumors:
We have developed several inducible
mouse brain tumor models by introducing frequently found genetic mutations in
human patients. We consider the inducible model a better model to recapitulate
the human glioblastoma, and it will be
extremely interesting to further investigate the cellular and molecular changes
before detectable brain tumor formation
in this particular model.
Normal and Neoplastic CNS Stem Cells (A240)
German Cancer Research Center
Im Neuenheimer Feld 581
69120 Heidelberg
Phone: +49 6221 42 3266
[email protected]
ESSENTIAL PUBLICATIONS:
(1.) Feng W. et al. (2013). The chromatin remodeler
CHD7 regulates adult neurogenesis via activation of
SoxC transcription factors. Cell Stem Cell, 13, 62–72.
(2.) Liu H-K. et al. (2010). The nuclear receptor tailless
induces long-term neural stem cell expansion and
Future Outlook:
We have generated several mouse models
which can be used to introduce genetic mutations specifically in NSCs. We are currently using these models to study:
1. Genetic and epigenetic regulation of neural stem cells:
Epigenetic mechanisms are crucial for the
regulation of the most important characteristics of stem cells that are self-renewal and multipotency.
Key transcriptional factors play decisive
roles in the determination of the iden-
Research at DKFZ 2014
brain tumor initiation. Genes Dev ,24, 683–695.
(3.) Liu H-K. et al. (2008). The nuclear receptor Tailless
is required for neurogenesis in the adult subventricular zone. Genes Dev, 22, 2473–2478.
(4.) Belz T. et al. (2007). Inactivation of the gene for
the nuclear receptor tailless in the brain preserving
its function in the eye. Eur J Neurosci, 26, 2222–2227.
A GFP labeled newborn
neuron in the mouse adult
hippocampus.
53
Cell and Tumor Biology
Vascular Signaling and Cancer
Helmholtz University Junior Research Group
Head: PD Dr. Andreas Fischer
Vascular Signaling and Cancer (A270)
German Cancer Research Center
Im Neuenheimer Feld 280
Blood vessels are a prerequisite for the maintenance of all organ functions. Embryogenesis is dependent on the development and
outgrowth of blood vessels, which provide the
organism with oxygen and nutrients. Sprouting angiogenesis occurs rarely in the adult
organism but can be observed for example
during wound healing and also in cancer. Thus,
a detailed knowledge about factors regulating angiogenesis and genetic networks, which
provide a functional quiescent vascular bed,
is highly desirable. Besides the formation of
new blood vessels, maintenance of existing
blood vessels is also essential. Endothelial cells
provide the inner lining of all blood vessels.
Disturbed endothelial cell functions are implicated in the pathogenesis of several cardiovascular diseases. Importantly, tumor growth and
metastasis are strictly dependent on vascular
growth and remodeling.
69120 Heidelberg
Phone: +49 6221 42 4150
[email protected]
Future Outlook:
Our research group investigates signaling
pathways that keep blood vessels in a resting but fully functional state. We examine the
signaling interplay between endothelial cells
as well as interactions of endothelial cells with
pericytes and tumor cells. Using cell culture
and animal models, our research will help to
better understand how genetic factors coordinate angiogenesis in the adult organism. We
investigate the role of Delta-Notch signaling
and other genes, which are implicated in the
formation of vascular malformations and vascular tumors. Other projects in our group focus
on barrier functions of blood vessels, which
are essential to control the passage of tumor
cells and fluids through the vessel wall. A novel
research approach deals with the question of
how genetic alterations in the endothelium
affect metabolism and are implicated in the
pathogenesis of cardiovascular diseases. Our
research work aims at identifying critical molecular and cellular mechanisms of cardiovascular diseases and tumor progression. These
findings will help to lay the foundation for the
development of innovative pharmacological
strategies.
ESSENTIAL PUBLICATIONS:
(1.) Wüstehube J. et al. (2010). Cerebral cavernous malformation protein CCM1 inhibits sprouting angiogenesis by activating DELTA-NOTCH signaling. Proc Natl
Acad Sci U S A., 28, 12640–12645.
(2.) Brütsch R. et al. (2010). Integrin cytoplasmic domain-associated protein-1 attenuates sprouting angiogenesis. Circ Res., 5, 592–601.
(3.) Adam M.G. (2013). Synaptojanin-2 binding protein
stabilizes the Notch ligands DLL1 and DLL4 and inhibits sprouting angiogenesis. Circ Res., ePub Sep. 11.
(4.) Fischer A. et al. (2004). The Notch target genes
Small blood vessels of the
retina with some covered by
pericytes (black).
54
Research Program
Hey1 and Hey2 are required for embryonic vascular
development. Genes Dev., 8, 901–911.
Cell and Tumor Biology
Stress-induced Activation of Hematopoietic
Stem Cells
HI-STEM Junior Research Group
Head: Dr. Marieke Essers
Tissue stem cells are responsible for the maintenance and repair of most organs and tissues.
In the hierarchically organized blood system,
dormant hematopoietic stem cells (HSCs) with
life long self-renewal capacity are at the top of
this hierarchy of cell types which give rise to
active HSCs that typically control the blood cell
production during healthy homeostasis. However, under conditions of stress, such as during
virus infections or after blood loss, where large
amounts of mature blood cells are lost, feedback signals are thought to signal back to the
dormant HSCs, leading to their activation and
thus production of new mature blood cells.
However, the molecular and cellular mechanisms, including those cytokines as a part of
these feedback loops, remain largely unexplored. Our work has recently demonstrated
that the cytokine IFNα which is produced by
virally infected immune cells to block the infection of more mature blood cells, is able to
activate the entire HSC pool including dormant
ones. One of the goals of our research is to
investigate the mechanism of IFNα-mediated
activation of HSCs and the potential role of
the surrounding bone marrow stem cell niche
in this process. Furthermore, we are currently
exploring feedback loops in response to other
stress situations, like bacterial infection and response to chemotherapy induced cytopenia.
Future Outlook:
Leukemias are initiated and maintained by leukemic stem cells (LSCs), which can transplant
the disease and show unlimited self-renewal
activity. Most importantly, LSCs appear to be
resistant to conventional therapies including
anti-proliferative chemotherapy. The mechanisms responsible for this resistance remain
unclear, however, their often dormant status
as well as their localization in protecting stem
cell niches are likely critical components. In
our group we address whether LSCs can be
targeted by driving them out of dormancy and
mobilize them out of their niche. Our finding
that IFNα activates normal HSCs to self-renew
by putatively altering their niche interactions,
may open new possibilities to combine this
Research at DKFZ 2014
drug with tyrosine kinase inhibitors such as
Imatinib/Gleevec. This class of targeted therapies can achieve long term remission by eliminating progenitor and mature leukemic cells
(as with chemotherapy alone), but spare the
LSCs (see figure) and thus do not lead to cure.
Using mouse models for leukemia and by testing leukemic patient samples, we are currently
exploring whether combination therapies with
IFNα or other activators can be developed to
also target LSCs and thus potentially cure the
disease.
ESSENTIAL PUBLICATIONS:
(1.) Essers M.A. et al. (2009). IFNalpha activates dormant haematopoietic stem cells in vivo. Nature, 458,
904–908.
(2.) Trumpp A. et al. (2010). Awakening dormant
haematopoietic stem cells. Nat Rev Immunol., 10,
Stress-induced Activation of Hematopoietic
Stem Cells (A011)
201–209.
German Cancer Research Center and
(3.) Essers M.A. et al. (2010). Targeting leukemic stem
cells by breaking their dormancy. Mol Oncol., 4, 443–
450.
(4.) Glauche I. et al. (2012). Therapy of chronic myeloid
leukaemia can benefit from the activation of stem
cells: simulation studies of different treatment combinations. Br J Cancer, 106, 1742–1752.
Heidelberg Institute for Stem Cell Technology
and Experimental Medicine
(HI-STEM gGmbH)
Im Neuenheimer Feld 280
69120 Heidelberg
Phone: +49 6221 42 3919
[email protected]
a.
dHSC
dLSC
+chemotherapy
G0
dHSC
dLSC
G0
‘resistant’
b.
dLSC
+IFNα
+chemotherapy
aLSC
???
G0
Like normal hematopoietic stem cells (HSCs), most leukemic stem cells (LSCs) are resistant to antiproliferative chemotherapy (a). Their resistance is believed to be the cause of relapse of the leukemia.
Several reasons for this resistance have been suggested, one of them being the dormant status of
LSCs. Thus, if dormancy is a main reason for LSC resistance to chemotherapy, one can postulate a
two-step therapy model by which the dormant LSCs can be targeted; activation of dormant LSCs by
activators of quiescence such as IFNa, followed by targeted chemotherapy (b). Such a therapy would
not only reduce the bulk of the leukemia, but also eliminate the dormant LSCs, thus reducing the
chances of a relapse of the leukemia.
55
Cell and Tumor Biology
Experimental Hematology
HI-STEM Junior Research Group
Head: Dr. Michael Milsom
Experimental Hematology (A012)
German Cancer Research Center and
Heidelberg Institute for Stem Cell Technology
and Experimental Medicine
(HI-STEM gGmbH)
Im Neuenheimer Feld 280
69120 Heidelberg
Transplantation of hematopoietic stem cells
(HSC) is a potential curative therapy for many
inherited blood disorders and, in concert with
high dose chemo- or radiotherapy, can be effective in the treatment of a range of cancers.
A major limitation of this approach is the lack
of availability of an immunologically matched
HSC donor. The work of the Experimental Hematology Group focuses on dissecting the biology of HSC in order to facilitate the production of transplantable HSC from novel sources,
and to better understand the regulation of
both normal and leukemic stem cells at the
molecular level. To these ends, we have developed several novel model systems to screen for
cellular factors that either have a major impact
on the formation of HSC during development
(HSC specification); or which regulate the ability of HSC to give rise to daughter cells that
have the same stem cell properties as the parent cell (HSC self-renewal). The latter process is
essential for the maintenance and expansion
of HSC numbers and is also deregulated in leukemic stem cells. In order to interrogate HSC
self-renewal, we primarily focus upon the comparative biology of HSC isolated from normal
wild type mice versus those from mice that are
deleted for genes in the Fanconi anemia sig-
nalling pathway. This model system allows us
to directly compare normal versus deregulated
HSC self-renewal.
Future Outlook:
As we gradually dissect the mechanisms that
regulate HSC biology, we anticipate that this
knowledge will have a direct impact upon both
our understanding of cancer and its treatment
in the clinic. Normal adult stem cells and cancer cells have a number of features in common
(unlimited proliferation capacity, restricted
differentiation, drug resistance) and understanding which signalling pathways mediate
these biological processes should allow us to
identify new therapeutic targets to eliminate
or restrict tumor cell growth. Our focus on
how normal stem cells regulate their genetic
integrity (using the Fanconi anemia model)
gives us new insight into how tumor cells may
evolve from normal healthy cells, which in turn
may allow us to advance strategies employed
in preventative medicine. Finally, by developing new methodologies to manipulate, expand
and differentiate stem cells, we can significantly contribute to the emerging field of cell and
gene therapy, which is showing some promise
in early clinical trials directed against a number of diseases, including cancer.
Phone: +49 6221 42 3920
ESSENTIAL PUBLICATIONS:
[email protected]
(1.) Geiselhart A. et al. (2012). Disrupted signalling
through the Fanconi anemia pathway leads to dysfunctional hematopoietic stem cell biology: underlying mechanisms and potential therapeutic strategies. Anemia, 2012: 265790.
The in vitro specification of
hematopoietic progenitor cells
from murine embryonic stem
cells. Using this methodology,
ES cells are able to differentiate
into a range of hematopoietic
progenitor cell types including
myeloid precursors such
as colony forming unit
granulocyte/macrophage
(CFU-GM) and erythroid
precursors such as erythroid
burst forming units (BFU-E).
56
Research Program
(2.) Müller L.U.W. et al. (2012). Overcoming reprogramming resistance of Fanconi anemia cells. Blood. 119
(23):pp5449-57.
(3.) Milsom M.D. et al. (2009). Ectopic HOXB4 overcomes the inhibitory effects of tumor necrosis
factor-α on Fanconi anemia hematopoietic stem and
progenitor cells. Blood, 113 (21): pp5111-20.
(4.) Milsom M.D. et al. (2009). Fanca-/- hematopoietic
stem cells demonstrate a mobilization defect which
can be overcome by administration of the Rac inhibitor NSC23766. Haematologica, 94 (7): pp1011-15.
Cell and Tumor Biology
Biomarker Discovery
HI-STEM Junior Research Group
Head: Dr. Christoph Rösli
Targeted cancer therapeutics, such as imatinib
and rituximab, have shown striking success in
the therapy of blood cancers. Unfortunately,
the majority of cancer patients still have to be
treated with conventional, unspecific chemotherapeutics. Due to their systemic distribution, these therapies carry severe side effects.
The disadvantages of conventional chemotherapeutics could be circumvented by the
targeted delivery of bioactive molecules to
the tumor. Drugs can be exclusively delivered
to disease sites by conjugation to molecules
specifically binding to tumor-associated biomarkers. Such ligand-based vascular targeting
strategies crucially rely on:
1) the identification of robust vascular-accessible tumor biomarkers,
2) the availability of antibodies or fragments
thereof with high affinities to these tumorspecific biomarkers and
3) the coupling of these antibodies to bioactive
moieties.
The HI-STEM/DKFZ-Junior Research Group
“Biomarker Identification” is focusing on the
mass spectrometry-based identification of
novel biomarkers expressed in tumorous tissue and/or metastases using advanced cell
culture systems, xenograft tumor models and
clinical samples. Furthermore, the selection of
human monoclonal antibodies against these
biomarkers for the development of targeted
cancer therapies and novel diagnostic tools is
a core technology in the laboratory.
re-occurrence of tumors years after successful treatment. Due to the lack of information
about the cell surface proteome of cancer
stem cells, no current therapeutic specifically
affects this highly aggressive but well-protected cancer cell population. Our group will
use its established chemical proteomics-based
methods for the identification of cell surface
biomarkers on the rare population of cancer
stem cells. The resulting biomarkers are then
used to develop high affinity human monoclonal antibodies by means of the phage display
technology. These antibodies are then not only
used for basic research, but also for the development of diagnostics and novel innovative
targeted therapeutics. Future cancer therapies
might then be based on a two phase protocol:
a first debulking phase for the reduction of the
tumor burden, followed by a targeted attack
on remaining, dormant cancer stem cells hidden elsewhere in the body.
Biomarker Discovery (A013)
ESSENTIAL PUBLICATIONS:
(1.) Fugmann T. et al. (2010). DeepQuanTR: MALDI-MSbased label-free quantification of proteins in complex biological samples. Proteomics, 10, 2631–2643.
(2.) Schliemann C. et al. (2010). In vivo biotinylation
of the vasculature in B-cell lymphoma identifies BST-
German Cancer Research Center and
Heidelberg Institute for Stem Cell Technology
and Experimental Medicine
(HI-STEM gGmbH)
Im Neuenheimer Feld 280
2 as a target for antibody-based therapy. Blood, 115,
69120 Heidelberg
736–744.
Phone: +49 6221 42 3917
(3.) Fugmann T. et al. (2011). Proteomic identifica-
[email protected]
tion of vanin-1 as a marker of kidney damage in a rat
model of type 1 diabetic nephropathy. Kidney Int., 80,
272–281.
Future Outlook:
During recent years, the concept of cancer
stem cells has evolved and is now widely accepted. Cancer stem cells (or tumor initiating
cells) are a small subpopulation of cancer cells
able to promote new tumors and to induce
metastases. Importantly, these cells are usually not reached by current cancer therapeutics
since they can reside (just like their healthy
counterparts), at least transiently, in a dormant, therapy-resistant phase. The population of transiently dormant cancer stem cells
is furthermore most likely responsible for the
Research at DKFZ 2014
(4.) Rösli C. et al. (2009). Comparative analysis of the
membrane proteome of closely related metastatic and nonmetastatic tumor cells. Cancer Res., 69,
5406–5414.
Following the proteomics-based
identification of a tumor-associated
biomarker, human monoclonal
antibodies are selected and used for
the development of novel diagnostic
tools and/or targeted therapeutics.
57
Cell and Tumor Biology
Metastatic Niches
HI-STEM Junior Research Group
Head: Dr. Thordur Oskarsson
Metastatic Niches (A014)
German Cancer Research Center and
Heidelberg Institute for Stem Cell Technology
and Experimental Medicine
(HI-STEM gGmbH)
Im Neuenheimer Feld 280
69120 Heidelberg
Phone: +49 6221 42 3903
[email protected]
Metastasis is the spread of cancer cells from
their site of origin leading to outgrowth in
distant organs and is the cause of most cancer
related deaths. To progress into overt metastasis, disseminated cancer cells must resist a
non-permissive environment and maintain
viability and growth at distant sites. Increasing evidence suggests that cancer cells adapt
by engaging and manipulating the microenvironment generating a metastatic niche
that promotes cancer cell fitness. To study the
metastatic niche the Oskarsson lab utilizes 3D
culture systems of primary cancer cells, RNA
interference, transcriptomic and proteomic
screens and various mouse models of cancer
progression and metastasis. We have shown
that tenascin C (TNC), an extracellular matrix
(ECM) protein expressed in normal stem cell
niches, is an important component of the metastatic niche and advances metastatic progression in breast cancer. The production of TNC
promotes viability of metastasis initiating cells
by enhancing the expression of musashi-1, a
positive regulator of Notch signaling and by
inducing the Wnt target gene LGR5. We are
currently dissecting further the pathways
modulated by TNC and studying the surface
receptors that TNC engages. Moreover, we are
analyzing the signaling and functional role of
other metastatic niche components in cancer
progression with a focus on the ECM. These
studies may provide valuable insights into cancer progression and could reveal new targets
for therapeutic intervention.
Future Outlook:
Our aim is to identify new components of the
metastatic niche and to characterize the interaction of cancer stem cells with the niche.
The objective is to determine how the niche
supports and maintains metastatic stem cell
characteristics and to study the possible role of
the niche in resistance to cancer therapy. It is
increasingly evident that stem cell properties
play an important role in metastasis development and the niche may support and maintain
these features. We will pay particular attention to the extracellular matrix that has been
demonstrated by us and others to be an essential component of the metastatic niche. The
function of the ECM extends greatly beyond a
structural scaffold and has been shown to be
important for cell regulation and modulation
of signaling pathways. The ECM components
of the metastatic niche support essential functions in cancer progression and effectively help
cancer cells to colonize distant organs. Moreover, the metastatic niche may be a mode for
disseminated cancer cells to resist therapeutic
intervention. We will analyze the role of niche
components in resistance to cancer therapy,
an attribute that is tightly linked to metastatic progression. The dissection of the metastatic niche and the ECM mediated signaling
within the niche, could provide new avenues to
therapeutically impair the competence of disseminated cancer cells and prevent metastatic
relapse.
ESSENTIAL PUBLICATIONS:
(1.) Acharyya S. et al. (2012). A CXCL1 paracrine network links cancer chemoresistance and metastasis.
Cell. 150, 165–178.
(2.) Oskarsson T. et al. (2011). Breast cancer cells produce tenascin C as a metastatic niche component to
colonize the lungs. Nat Med. 17, 867–874.
(3.) Oskarsson T. et al. (2010). Diverted total synthesis leads to the generation of promising cell-migration inhibitors for treatment of tumor metastasis: in
vivo and mechanistic studies on the migrastatin core
Immunostaining of lung metastasis in breast
cancer xenograft showing expression of the
metastatic niche component tenascin-C at
the invasive front (arrow heads).
58
Research Program
ether analog. J Am Chem Soc., 132, 3224–3228.
(4.) Tavazoie S.F. et al. (2008). Endogenous human microRNAs that suppress breast cancer metastasis.
Nature., 451, 147–152.
Cell and Tumor Biology
Synaptic Signalling and Neurodegeneration
DZNE-Junior Research Group
Head: Dr. Jakob von Engelhardt
Our group investigates glutamatergic synaptic
transmission in the hippocampus and cortex.
We are particularly interested in what role different glutamate receptors (AMPA- and NMDAreceptors) and glutamate receptor-interacting
proteins play in physiological and pathophysiological processes. AMPA receptors mediate
most of the fast excitatory transmission in the
central nervous system. NMDA receptors are
important for synaptic plasticity and thus for
learning and memory. In addition, excessive
activation of NMDA receptors is detrimental
for neurons (excitotoxicity) and contributes to
the pathophysiology of brain diseases such as
stroke and neurodegenerative diseases.
of great importance for all cognitive processes. AMPA-receptor interacting proteins (TARPs, CKAMP44, cornichons and
SynDig1) regulate receptor localization
and function. We will use heterologous
expression systems and transgenic mice
to analyze the influence of those proteins
on the electrophysiological properties and
localization of AMPA-receptors.
ESSENTIAL PUBLICATIONS:
(1.) von Engelhardt J. et al. (2011). 5-HT3A Receptor-Bearing White Matter Interstitial GABAergic Interneurons Are Functionally Integrated into Cortical
and Subcortical Networks. J Neurosci, 31, 16844–
16854.
Future Outlook:
1. Mechanisms of Amyloid β pathology:
One of the hallmarks of Alzheimer’s
disease is the accumulation of amyloid
beta-peptide (Aβ) in the brain and its
deposition as plaques. However, the current prevailing view is that soluble oligomeric Aβ is one of the main mediators of
Alzheimer neurotoxicity, rather than the
plaques. There are indications that glutamate receptors play a role in Aβ-mediated
neurotoxicity. We will use glutamate receptor transgenic mice to investigate the
influence of this interaction on the physiology and anatomy of hippocampal and
cortical neurons.
2. Regulation of synaptic communication via
AMPA-receptor interacting proteins:
Precise control of AMPA receptor number
and localization on the cell membrane
regulates synaptic strength and is thus
Research at DKFZ 2014
(2.) von Engelhardt J. et al. (2010). CKAMP44: a brainspecific protein attenuating short-term synaptic
plasticity in the dentate gyrus. Science, 327, 1518–1522.
(3.) Korotkova T. et al. (2010). NMDA receptor ablation on parvalbumin-positive interneurons impairs
hippocampal synchrony, spatial representations, and
working memory. Neuron, 68, 557–569.
(4.) von Engelhardt J. et al. (2008). Contribution of
Synaptic Signalling and Neurodegeneration
(A300)
hippocampal and extra-hippocampal NR2B-contain-
German Cancer Research Center
ing NMDA receptors to performance on spatial learn-
Im Neuenheimer Feld 280
ing tasks. Neuron, 60, 846–860.
69120 Heidelberg
DZNE = German Center for Neurodegenerative
Diseases within the Helmholtz Association
Phone: +49 6221 423105
[email protected]
Schematic representation of the 424
residue CKAMP44 protein, with signal
peptide (SP), extracellular domain
with cysteine-rich region (C’s), single
transmembrane region (TM) and
intracellular domain containing a
PDZ domain interaction site at the
C-terminus. The extracellular cysteinerich region with proposed disulfide
bridges of a Cystine-knot is shown below.
The in situ hybridizations illustrate
that CKAMP44 mRNA is expressed in
the brain of embryonic day 19 (E19),
postnatal day 15 (P15) and adult mice. The
immunocytochemical analyses of cultured
neurons show that CKAMP44 is expressed
in dendritic spines and co-localizes with
AMPA receptor subunits GluA2/3.
59
Coordinator
PROF. DR. ROLAND EILS
Structural and
Functional Genomics
Cancer arises when genes in a cell are changed in such a way that
they cause the cell to divide uncontrollably or to resist cell death.
However, for this to occur a multitude of specific changes have to
coincide. It is the task of this research program to analyze the genome, i.e., the complete set of genes and its products, in order to lay
the foundation for developing new diagnostic and treatment methods. This involves mapping the genome, localizing genes within
the genetic material, and investigating the functions of cancerrelevant genomic areas. The vast amounts of data accumulated in
the process are being captured and evaluated using bioinformatic
methods. By combining approaches from mathematics, statistics,
physics, and computer sciences with computer-assisted simulation
techniques, the theoretical groups within the research program are
bridging the gap to experimental research. The methods developed are then directly utilized in many areas within collaborations
between numerous DKFZ divisions, other external research groups
and clinical partners.
60
Research Program
Research at DKFZ 2014
61
Structural and Functional Genomics
Biophysics of Macromolecules
Division
Head: Prof. Dr. Jörg Langowski
Biophysics of Macromolecules (B040)
German Cancer Research Center
Im Neuenheimer Feld 280
69120 Heidelberg
Phone: +49 6221 42 3390
[email protected]
Gene activity is not determined by the DNA sequence alone, but also by its three-dimensional organization in the cell: DNA and chromatin
global structure play a crucial role in the regulation of many important biological processes,
such as cell differentiation or cancerogenesis.
The main goal of our research is to study the
three-dimensional structure and dynamics of
the genome in normal and tumor cells and to
describe it by quantitative models. This will
help us understand the connection between
genome structure and normal or pathological
states of the cell. To this aim, we study longrange interactions in DNA when genes are regulated by transcription factors, the structure
of nucleosomes and chromatin fiber, and the
organization of chromosome territories in the
living cell nucleus. The experiments are supplemented by advanced computer simulation
techniques that describe the organization of
DNA and chromatin as a flexible polymer.
Biophysical methods used include in particular
single-molecule techniques (fluorescence correlation spectroscopy, single pair FRET, scanning force microscopy), advanced imaging (single plane illumination microscopy), light and
neutron scattering, analytical ultracentrifugation, absorption and fluorescence spectroscopy, and stopped flow kinetics. We also provide
biophysical methods for the characterization
of other systems of biological macromolecules,
especially in protein-protein and protein-DNA
interaction and intermediate filament proteins.
Future Outlook:
In the future, we shall develop our activities
in the fields of nucleosome and chromatin
dynamics and of intermediate filament (IF)
biophysics. Three major lines of research will
be followed:
1. the role of histone tails and their modifications in chromatin packaging (“molecular epigenetics”), using single molecule
FRET as a tool to characterize structural
transitions in nucleosomes;
2. the dynamics of protein transport in the
living cell nucleus, using our newly developed SPIM microscopy techniques with
ultra-fast detection;
3. the dynamics of assembly of IF proteins
and the biophysical characterization of
their structure and flexibility.
We shall continue to build up our computer
simulation activities, ranging from modelling biomolecules in atomic detail to coarsegrained models of the genome architecture in
entire cell nuclei. This theoretical aspect will
always form an important complement to our
experimental research. The ultimate goal is to
design a physical model of the entire cell in
time and space, which can contribute to the
understanding of cancer development and to
its therapy. Our research shall be a step on the
way there.
ESSENTIAL PUBLICATIONS:
(1.) Fritsch C. et al. (2011). Chromosome dynamics, molecular crowding and diffusion in the interphase
cell nucleus: A Monte-Carlo lattice simulation study.
Chromosome Research, 19, 63–81.
(2.) Böhm V. et al. (2010). Nucleosomal DNA accessibility governed by the dimer/tetramer interface. Nucleic Acids Research, 39, 3093–3102.
(3.) Gansen A. et al. (2009). Nucleosome disassembly
intermediates characterized by single-molecule FRET.
Proc. Natl. Acad. Sci. USA 11, 15308–15313.
(4.) Vámosi G. et al. (2008). Conformation of the c-
Mobility map of EGFP-protein in a living HeLa cell
(Source: Dross N, Spriet C, Zwerger M, Müller G,
Waldeck W, Langowski J. (2009) Mapping eGFP
Oligomer Mobility in Living Cell Nuclei. PLoS ONE
4(4): e5041).
62
Research Program
Fos/c-Jun complex in vivo: a combined FRET, FCCS, and
MD-modeling study. Biophys J., 94, 2859–2868.
Structural and Functional Genomics
Systems Biology of Cellular Signal Transduction
Division
Head: Prof. Dr. Ursula Klingmüller
The goal of the division is to gain insights into
molecular mechanisms that regulate cellular decisions and to address their impact on
behavior at the tissue and organ level. When
these control mechanisms fail, cancer and
other diseases arise. Cellular responses are
regulated by a multitude of extracellular signals received by cell surface receptors. Within
cells the information is processed through
complex intracellular signaling networks that
in turn impinge on gene regulation and affect
metabolism to finally coordinate physiological
responses such as proliferation, survival and
differentiation. These responses operate on
very different time scales ranging from minutes to hours and days. Thus, it is essential to
examine key dynamic properties of biological
systems, which can be addressed by combining
the generation of quantitative time-resolved
data with mathematical modeling. Data-based
mathematical models enable rapid testing of
hypotheses to uncover deregulation in cancer
and to predict strategies of intervention in
diseases. In close collaboration with modeling
partners, methods for quantitative analysis of
signaling networks were developed and multiple dynamic pathway models were established
yielding unexpected insights into regulatory
mechanisms of signaling pathways. The main
projects of the division address:
1.
2.
3.
Unraveling principal mechanisms of
erythropoietin (Epo)-mediated cellular
decisions in the hematopoietic system.
Bridging from the cellular to the whole
organ level during liver regeneration.
Insights into altered regulation in cancer
and prediction of strategies for efficient
intervention in diseases (cancer, drug-in
duced liver injury, viral infection).
Research at DKFZ 2014
Future Outlook:
This knowledge will be used to establish integrated models of signaling pathways, to
link them to gene regulation as well as cellcell communication and to include cell cycle
progression and cell survival. Finally, integration into multi-scale models and whole body
models is aspired. Translational aspects are
strengthened through intensive collaborations with clinical partners and companies in
the frame of large third party funded research
networks.
ESSENTIAL PUBLICATIONS:
(1.) Schilling M. et al. (2009). Theoretical and experimental analysis links isoform-specific ERK signalling
to cell fate decisions, Mol Sys Biol, 334: 119–136.
(2.) Becker V. et al. (2010). Covering a broad dynamic
Systems Biology of Cellular Signal
Transduction (B200)
range: information processing at the erythropoietin
German Cancer Research Center
receptor. Science, 328: 1404–1408.
Im Neuenheimer Feld 280
(3.) Raia V. et al. (2011). Dynamic mathematical mode-
69120 Heidelberg
ling of IL13-induced signaling in Hodgkin and primary
mediastinal B-cell lymphoma allows prediction of
therapeutic targets. Cancer Res., 71: 693–704.
Phone: +49 6221 42 4481
[email protected]
(4.) Bachmann J. et al. (2011). Division of labor by dual
feedback regulators controls JAK2/STAT5 signaling
over broad ligand range. Mol Syst Biol. 7: 516.
In erythroid progenitor cells the cell
membrane is visualized by staining
for transferrin receptor expression
(green) and the nucleus by staining
for DNA content (blue).
63
Structural and Functional Genomics
Molecular Genome Analysis
Division
Head: Prof. Dr. Stefan Wiemann
Molecular Genome Analysis (B050)
German Cancer Research Center
Cancer and other human diseases arise from
genetic aberrations that are either inherited
or occur – as in most cancers – spontaneously
in somatic cells. These defects cause abnormal activities of gene products that lead to
malfunctioning of molecular and cellular interactions which, in consequence, may induce
tumors and cause cancer progression.
The central objective of our division is to understand the complex molecular mechanisms
that have evolved in the regulation of signaling networks and how these impact on cancer
development, metastasis, and drug resistance. To this end, we generate and maintain
resources for large-scale experimentation,
apply high-throughput functional genomics and proteomics technologies, and analyze
candidate genes using in vitro as well as in vivo
systems. Effects of perturbations (gene gainand loss-of-function, miRNA, drugs) imposed
on the signaling processes are experimentally
tested and then computationally modeled.
This generates mechanistic knowledge that
is exploited to identify new diagnostic and
prognostic markers as well as to develop novel
Im Neuenheimer Feld 580
69120 Heidelberg
Phone: +49 6221 42 4646
[email protected]
strategies for therapeutic intervention. Our
major focus here is on breast cancer, where we
investigate protein and non-protein factors
that are involved in the progression of different subtypes via their activities in interrelated
signaling networks.
Future Outlook:
Our future research is mostly in two directions.
We have already seen from our current data
that signaling is not regulated in isolated
pathways, but rather in complex networks.
Therefore, in the future we will investigate the
impact individual perturbations have in a variety of cellular pathways and at different levels
(DNA, RNA, protein, metabolite, …, phenotype).
This should provide us with a better understanding of the connectivity in multi-layer interaction systems. Such information will be essential, for example, to identify strategies that
should help to overcome drug resistance
While much of our current knowledge is based
on in vitro experiments, we need to validate
findings in vivo in order to prove their relevance. To this end, we will generate and test
animal models and challenge our hypotheses
with patient samples. Collaborations to this
end have been established and first promising
results have already been obtained.
ESSENTIAL PUBLICATIONS:
(1.) Ward A. et al. (2013). Re-expression of microRNA375 reverses both tamoxifen resistance and accompanying EMT-like properties in breast cancer. Oncogene,
32, 1173–82, doi:10.1038/onc.2012.1128.
Elucidating the regulation of
signaling via miRNAs. Breast cancer
cells were transfected with a library
of 810 human miRNA mimics and
induced effects were analyzed by
quantitative analysis of proteins
in the EGFR signaling network.
Thus activating and inhibiting
effects on protein abundance could
be identified (A). This led to the
identification of proteins (blue)
being co-regulated by several
miRNAs (orange), as well as miRNAs
co-regulating several proteins (B).
Activating edges are in red, inhibiting
edges in green.
64
Research Program
(2.) Götschel F. et al. (2013). Synergism between
Hedgehog-GLI and EGFR Signaling in HedgehogResponsive Human Medulloblastoma Cells Induces Downregulation of Canonical Hedgehog-Target
Genes and Stabilized Expression of GLI1. PLoS One,
8(6): e65403.
(3.) Uhlmann S. et al. (2012). Global microRNA level
regulation of EGFR-driven cell-cycle protein network
in breast cancer. Mol Syst Biol, 8, 570.
(4.) Keklikoglou, I. et al. (2012). MicroRNA-520/373
family functions as a tumor suppressor in estrogen
receptor negative breast cancer by targeting NF-kappaB and TGF-beta signaling pathways. Oncogene,
doi:10.1038/onc.2012.1128.
Structural and Functional Genomics
Molecular Genetics
Division
Head: Prof. Dr. Peter Lichter
Our laboratory applies oncogenomic approaches for the elucidation of pathomechanisms of tumor etiology and progression and
for the identification of prognostic and predictive genes and gene-signatures. To this end, we
perform large screens by using comprehensive molecular profiling technologies revealing
tumor-cell alterations at the level of the genome, the transcriptome and the epigenome.
Integration of such data sets with clinical data
allows us to identify candidate genes which
are subsequently tested for their i) possible
role in tumor pathomechanisms, ii) potential
as target for novel therapy-strategies, iii) prognostic value to stratify patient subgroups for
risk-adapted therapy regimens and iv) potential to predict therapy response or resistance
in cancer patients. Major accomplishments of
the last 5 years: We have greatly contributed to
novel tumor sub-classification schemes that
allow stratification of cancer patients for different therapy regimens on the basis of the
genetic tumor profiles. We have assessed predictive gene signatures in a clinical treatment
trial testing neo-adjuvant protocols in breast
cancer. Through the identification of pathogenically relevant genes, we have identified
candidate targets for the development of novel therapies, in particular in human leukemia,
head and neck tumors, gliomas and colorectal
cancer. Through the functional characterization of candidate genes we also developed
pre-clinical models for the testing of novel
therapies.
also extended to other tumor entities. Furthermore, we wish to implement a strategy for the
establishment of cancer genome sequencing in a clinical diagnostic setting, following
a three-step procedure: i) sequencing of 50 to
100 candidate genes of oncogenic relevance in
large series of tumors accompanying existing
treatment trials, ii) sequencing of the entire
exome of respective tumor cases, and iii) sequencing of whole genomes of selected cases
and assessment of the conditions for whole
genome sequencing in future comprehensive
diagnostic setting. Candidate genes, for which
we have established a pathogenic role in carcinogenesis, are currently being tested in preclinical in vitro and in vivo models using known
inhibitors. We plan to complement these studies by the isolation of novel inhibitors exploiting the DKFZ/EMBL core facility for the screening of small molecular libraries as well as the
screening of biological extracts through dedicated scientific collaborations. A third focus is
the transfer of biomarkers in gene signatures
into clinical settings through prospective diagnostic trials, preferably associated to current
treatment trials.
ESSENTIAL PUBLICATIONS:
Molecular Genetics (B060)
German Cancer Research Center
Im Neuenheimer Feld 280
69120 Heidelberg
Phone: +49 6221 42 4619
[email protected]
(1.) Gronych J. et al. (2011). An activated mutant BRAF
kinase domain is sufficient to induce pilocytic astrocytoma in mice. J Clin Invest, 121, 1344–1348.
(2.) Barbus S. et al. (2011). Differential retinoic acid
signaling in tumors of long- and short-term glioblastoma survivors. J Natl Cancer Inst, 103, 598–606.
(3.) Seiffert M. et al. (2010). Soluble CD14 is a nov-
Future Outlook:
One of our major goals is to apply sequencing of the genomes of cancer cells to identify
the entire spectrum of genetic alterations that
may occur in a given tumor entity and to assess their clinical relevance. This is done with
special focus on pediatric brain tumors, but
el monocyte-derived survival factor for chronic lymphocytic leukemia cells, which is induced by CLL cells
in vitro, and present at abnormally high levels in vivo.
Blood, 116, 4223–4230.
(4.) Pfister S. et al. (2008). BRAF gene duplication constitutes a novel mechanism of MAPK pathway activation in low-grade astrocytomas. J Clin Invest, 118,
1739–1749.
Research at DKFZ 2014
65
Structural and Functional Genomics
Pediatric Neurooncology
Division
Head: Prof. Dr. Stefan Pfister
Pediatric Neurooncology is currently a vibrant field of research, with countless critical
achievements in recent years in understanding the molecular biology of childhood brain
tumors and translating molecular findings into
clinical practice. This is desperately needed
from a clinical perspective, since brain tumors
have become the number one cause of cancerrelated mortality in children. Our group aims
to bridge the gap between generating genomic screening data (microarray-based as well as
next-generation sequencing) and exploiting
these data for the sake of our patients. The
first goal includes the identification, validation and clinical application of prognostic and
predictive biomarkers in different childhood
brain tumors, including medulloblastoma,
ependymoma, pilocytic astrocytoma and glioblastoma. The second major focus involves the
systematic pre-clinical testing of novel smart
drugs, often in combination with established
cytotoxic drugs and/or chemotherapy, to treat
models (in vitro and in vivo), and ultimately
patients, based on the genetic/molecular signature of the individual tumor (“personalized
cancer care”).
Pediatric Neurooncology (B062)
German Cancer Research Center
Im Neuenheimer Feld 280
69120 Heidelberg
Phone: +49 6221 42 4618
[email protected]
and Department of Pediatric Hematology and
Oncology, Heidelberg University Hospital
Future Outlook:
The immense biological heterogeneity of childhood brain tumors between and within tumors, which is a prerequisite for targeted treatment approaches, is still poorly understood
und thus currently hindering such approaches
on a regular basis in the clinic. To overcome
this shortcoming, we will continue to comprehensively investigate the entire genetic
diversity of childhood brain tumors within and
across histopathological entities. A large and
continuously growing repertoire of preclinical
models will allow us to specifically test biological hypotheseses gained from genome-wide
primary tumor analyses in vitro and in vivo, before they are recommended for use in patients.
Another focus will be the analysis of clonality
within tumors, their respective metastases,
and tumor relapses, by ultra-deep next-generation sequencing techniques. This should allow
us to appropriately consider the biological importance of subclones already in the primary
tumor that confer tumor dissemination, local
re-growth, and therapy resistance. As a third
major focus, we have started focusing on the
detection of tumor-specific alteration in body
fluids, such as cerebrospinal fluid and plasma,
which can be exploited for molecular diagnostics, tumor cell clearance (minimal residual
disease), detection of molecular targets, and
primary resistance mechanisms.
ESSENTIAL PUBLICATIONS:
(1.) Bender S. et al. (2013). Reduced H3K27me3 and
DNA hypomethylation are major drivers of gene expression in K27M-mutant pediatric high-grade gliomas. Cancer Cell, accepted.
(2.) Jones DT. et al. (2013). Recurrent somatic alterations of FGFR1 and NTRK2 in pilocytic astrocytoma.
Nat Genet, 45, 927–932.
(3.) Sturm D. et al. (2012). Hotspot mutations in H3F3A
and IDH1 define distinct epigenetic and biological
Medulloblastoma showing
high level amplifications of
MYCN (red signal) and GLI2
(green signal) in different
cells of the same tumor.
66
Research Program
subgroups of glioblastoma. Cancer Cell, 22,
425–437.
(4.) Jones D.T. et al. (2012). Dissecting the genomic complexity underlying medulloblastoma. Nature,
488, 100–105.
Structural and Functional Genomics
Functional Genome Analysis
Division
Head: Dr. Jörg D. Hoheisel
Research at the Division of Functional Genome
Analysis focuses on the development and immediate application of new technologies for
analysis, assessment and description of both
the realisation and regulation of cellular function from genetic information. Analysis of
tumour material is the prime focus, with a particular emphasis on pancreatic cancer. Parallel
studies on an international scale are under
way, for example, on the epigenetic modulation of gene promoters, variations in transcription factor binding, changes at transcript levels
of coding and non-coding RNAs, differences in
the actual protein expression and the occurrence and ratio of protein isoforms, as well as
the intensity of protein interactions. From the
resulting data, we strive to understand cellular
regulation and its biological consequences. In
combination with clinical data, this knowledge
is used for the creation of a means of reliable,
possibly early and non-invasive diagnosis, accurate prognosis and patient stratification,
monitoring of treatment results and the establishment of new therapeutic approaches.
As a consequence of the immense amount of
information available at the level of nucleic
acids, developments and applications in the
field of affinity-based analysis of the proteome
have become a technology focus, since technological and analytical processes in this area
are still inadequate for many, in particular biomedical, purposes.
Future Outlook:
A more recent line of work aims at in vitro implementation of complex biological processes.
Our goal is utilisation in the area of synthetic
biology for the production of molecules and
the establishment of artificial molecular systems. Cell-free biosynthetic production will be
critical for many biotechnological and pharmacochemical challenges ahead. Artificial experi-
Research at DKFZ 2014
mental systems, on the other hand, will complement current systems biology, evaluating
biological models experimentally. Similar to
physics, insight into cellular functioning will be
gained by an iterative processing of information by experimental and theoretical systems
biology. Eventually, this may lead to the establishment of a fully synthetic self-replicating
system and, ultimately, an archetypical model
of a cell.
ESSENTIAL PUBLICATIONS:
(1.) Schröder C. et al. (2010). Dual-color proteomic profiling of complex samples with a microarray of 810
cancer-specific antibodies. Mol. Cell. Prot., 9, 1271–
1280.
(2.) de Souza Rocha Simonini P. et al.(2010). Epigenetically de-regulated microRNA-375 activates Estrogen
Receptor alpha activity in breast cancer. Cancer Res.,
70, 9175–9184.
(3.) Holtrup F. et al. (2011). Nemorosone specifically inhibits growth of pancreatic cancer cells and induces
Functional Genome Analysis (B070)
apoptosis via activation of the unfolded protein re-
German Cancer Research Center
sponse (UPR). Brit. J. Pharmacol., 162, 1045–1059.
Im Neuenheimer Feld 280
(4.) Fredebohm, J. et al. (2013). Depletion of RAD17
sensitizes pancreatic cancer cells to gemcitabine.
J. Cell Sci. ,126, 3380–3389.
69120 Heidelberg
Phone: +49 6221 42 4680
[email protected]
Protein profile of urine samples from
cancer patients and healthy donors.
Samples are depicted as squares
coloured according to disease-state
and gender; black spots represent
proteins that contribute to the
diagnosis. As can be seen from the
plot, discrimination between cancer
and healthy is nearly as good as
discrimination between men and
women.
67
Structural and Functional Genomics
Theoretical Bioinformatics
Division
Head: Prof. Dr. Roland Eils
Theoretical Bioinformatics (B080)
German Cancer Research Center
Im Neuenheimer Feld 580
69120 Heidelberg
Phone: +49 6221 42 3600
[email protected]
Using current DNA sequencing methods, it is
today feasible to determine the sequence of a
human individual (e.g. a patient suffering from
cancer) in a single day. Other complementary
technologies, such as epigenome, transcriptome, proteome or metabolome analysis,
deliver additional data with a great potential
for precise diagnostics. Given the enormous
technological advances in data generation, the
integration of these data in order to generate
new insights into complex biological functions is still a major challenge and can only be
achieved with interdisciplinary approaches.
Our division is developing computer-assisted
methods for interpreting complex genomic
and other biological data, as well as methods
for modeling and simulation of biological processes. Major activities include the development of integrated bioinformatic approaches
for the interpretation and management of
cancer genome and accompanying clinical
data, the application of state-of-the-art technologies in automated live-cell imaging and
image analysis, experimental and theoretical
systems biology approaches addressing key
cellular mechanisms and their distortions in
cancer cells, as well as the development of new
synthetic biology tools to manipulate cellular
processes. For this purpose, the division is integrating systems biology, automated image
processing, state of the art light-microscopy,
cell biology and bioinformatics.
Scheme representing the phenomenon of X
chromosome hypermutation. Cancer cells
from female patients carry significantly more
mutations (orange triangles) on the inactive
X-chromosome (left) than on the active
X-chromosome (right).
68
Research Program
Future Outlook:
Our overarching aim is the development of
new insights linking alterations in cancer, or
other diseased cells, with biological functions
in order to find new potential targets for improved diagnostics and treatment. Therefore,
we develop integrated platforms combining
bioinformatic data analysis and mathematical modeling of complex diseases processes. In
the future, these systems medicine platforms
will provide computer-assisted diagnostics and
therapy decision tools to support medical doctors in patient care.
ESSENTIAL PUBLICATIONS:
(1.) Jäger N. et al. (2013). Hypermutation of the Inactive X Chromosome Is a Frequent Event in Cancer.
Cell , 155, 1–15.
(2.) Jones DTW. et al. (2013). Recurrent somatic alterations of FGFR1 and NTRK2 in pilocytic astrocytoma.
Nat Genet, 45, 927–932.
(3.) Jones DTW. et al. (2012). On behalf of the ICGC
PedBrain Tumor Project. Dissecting the genomic complexity underlying medulloblastoma. Nature, 488,
100–105.
(4.) Neumann L. (2010). Dynamics within the CD95
death-inducing signaling complex decide life and
death of cells. Molecular Systems Biology, 6, 352.
Structural and Functional Genomics
Theoretical Systems Biology
Division
Head: Prof. Dr. Thomas Höfer
The division of Theoretical Systems Biology
pursues multidisciplinary research to understand how biological function emerges from
interacting components – molecules within a
cell and cells within an organism. Our work is
essentially collaborative and characterized by a
tight interplay between experimentation, data
analysis and mathematical modeling. We dissect the molecular switches that regulate the
proliferation and differentiation of T lymphocytes and thus, orchestrate adaptive immune
responses. The second focus of the division
is on growth-factor signaling and cell-cycle
control. We study the interplay of these processes in human tumor models to understand
how therapy resistance arises from synergistic
oncogene action. From both strands of work
common principles at the systems level are
emerging. Our work aims at identifying the
functional behavior of molecular networks in
the cell and at quantifying the control exerted
by individual components to inform novel
therapeutic approaches.
Future Outlook:
A key challenge of quantitative biology is to
understand the interplay between molecular modules – such as those controlling the
induction and maintenance of expression of
master transcription factors for cell fate – and
genome-wide programs that mediate coordinated cell function.
ESSENTIAL PUBLICATIONS:
(1.) Rand U. et al. (2012). Multi-layered cellular stochasticity and paracrine amplification shape the
type-I interferon response. Mol. Syst. Biol., 8, 584.
(2.) Luijsterburg M.S. et al. (2010). Stochastic and reversible assembly of a multiprotein DNA repair complex ensures accurate target site recognition and efficient repair. J. Cell Biol.,189, 445–463.
(3.) Busse D. et al. (2010). Competing feedback loops
shape IL-2 signaling between helper and regulatory T
cells in cellular microenvironments. Proc. Natl. Acad.
Theoretical Systems Biology (B086)
Sci. USA, 107, 3058–3063.
German Cancer Research Center
(4.) Schulz E. et al. (2009). Sequential polarization
Im Neuenheimer Feld 267
and imprinting of T-helper type 1 differentiation by
interferon-γ and interleukin-12. Immunity, 30, 678–
688.
69120 Heidelberg
Phone: +49 6221 54 51380
[email protected]
Tracking of
individual
tumor cells in
the fluorescence
microscope.
Research at DKFZ 2014
69
Structural and Functional Genomics
Signaling and Functional Genomics
Division
Head: Prof. Dr. Michael Boutros
Signaling and Functional Genomics (B110)
German Cancer Research Center
Im Neuenheimer Feld 580
69120 Heidelberg
Phone: +49 6221 42 1951
[email protected]
Cellular signaling systems control many key
decisions during development, stem cell maintenance and tumorigenesis. The focus of our
group is on the systematic dissection of signaling pathways to identify novel molecular processes and to understand how pathways connect in cellular networks. We use genetic and
genomic approaches for this purpose, but also
study specific processes at the molecular level
to probe underlying mechanisms. We pursue
two main lines of research:
1. Systematic analysis of Wnt signaling in
model organisms and tumor cells. Canonical and non-canonical Wnt signaling
play key roles during development and
tumorigenesis. Aberrant regulation of
Wnt signaling has been implicated in cancer, as exemplified by mutations in APC,
a negative regulator of Wnt signaling.
During the past years, our laboratory has
contributed to the molecular understanding of Wnt signaling by identifying novel
components and by the characterization
of Wnt-ligand specific cargo receptors.
2. Systems genetics and synthetic lethality.
Genetics underlying many phenotypes, including most common diseases, are complex with contributions from multiple loci.
The analysis of synthetic genetic interaction networks reveals how biological systems achieve a high level of complexity
with a limited repertoire of components.
We have established high-thoughput
methodologies to measure synthetic genetic interaction in model organisms and
cancer cells by RNAi.
Future Outlook:
We are interested in the systematic analysis of
synthetic genetic interactions to dissect genotype-phenotype relationships, with a particular
focus on combinatorial mapping approaches
using RNAi and small molecules. Interactions
between genetic variants may be one important explanation for the ‘missing heritability’
in genome-wide association studies. Extensive
interactions between different genetic alleles
with large effects on many phenotypes have
been documented in many model systems.
We will use quantitative phenotyping by highthroughput microscopy to measure synthetic
genetic interactions. Genetic interaction data
will be used to model cellular networks with a
particular focus on oncogenic signaling pathways. We will also develop novel technologies
required for miniaturization of cellular assays
and high-throughput imaging, for reproducible cell-based RNAi in primary cell types and
novel approaches to data integration. A second
area of interest is the in-depth analysis of Wnt
and interacting signaling networks in development, stem and tumor cells. We use a spectrum of model systems, from Drosophila to
mouse and human cancer cells to identify key
components and understand how they are embedded into physiological processes. For more
information, visit us at www.dkfz.de/signaling
ESSENTIAL PUBLICATIONS:
(1.) Horn T. et al. (2011). Mapping of signaling networks through synthetic genetic interaction analysis
by RNAi. Nature Methods, 8, 341–346.
(2.) Gross, J. C. et al. (2012). Active Wnt proteins are secreted on exosomes. Nature Cell Biology, 14, 1036–
1045.
(3.) Boutros M. & Ahringer J. (2008). The art and design of genetic screens: RNA interference. Nature Reviews Genetics, 9, 554–566.
(4.) Bartscherer, K. et al. (2006). Secretion of Wnt ligands requires Evi, a conserved transmembrane protein. Cell, 125, 523–33.
70
Research Program
Research at DKFZ 2014
By silencing genes using RNAi we can
analyse the genes’ effect in a quantitative
and high-throughput manner. In this
microscopy image of human cancer cells,
nuclei are shown in red, cell membranes in
green, and the cellular scaffolding in blue.
71
Structural and Functional Genomics
Signal Transduction in Cancer and Metabolism
Division
Head: Dr. Aurelio Teleman
Signal Transduction in Cancer and Metabolism
(B140)
When cancer cells proliferate to form a tumor,
they need to grow and to divide. Regulation of
cell division (i.e. the cell cycle) has been extensively studied. In comparison, the mechanisms
regulating cell growth (i.e. the accumulation
of cell mass) are less well understood. The Teleman lab studies cell growth and its regulation.
For cells to grow, they need to produce biosynthetic building blocks such as nucleotides,
amino acids and lipids. Consequently understanding cell growth requires understanding
metabolism. Cells decide to grow, however,
based on information coming from outside
the cell, such as the presence of nutrients and
growth factors. Cells receive and process this
information via signaling pathways such as
the insulin pathway. Consequently understanding cell growth also requires understanding signaling pathways. Finally, the signaling
pathways regulate the metabolic pathways,
therefore the lab also studies the interface
between signaling and metabolism. Both the
metabolic pathways, as well as the signaling pathways, are complex and intricate networks. These pathways, however, are conserved
amongst animals. The Teleman lab studies
these pathways using a combination of human tissue culture together with the fruitfly
Drosophila, since Drosophila is simplified and
genetically tractable compared to mammals.
Future Outlook:
The aim of our work is to understand the
processes regulating cell growth so that this
knowledge can be used in the future for cancer
therapy. Unlike other cells in the body, cancer
cells have mutations that promote cell growth.
Blocking this process will hopefully be a powerful method to specifically and efficiently inhibit tumor progression.
ESSENTIAL PUBLICATIONS:
German Cancer Research Center
(1.) Xu X. et al. (2012). Insulin signaling regulates fat-
Im Neuenheimer Feld 580
ty acid catabolism at the level of CoA activation. PLoS
Genetics, 8, e1002478.
69120 Heidelberg
(2.) Pallares C. et al. (2012). Tissue-specific coupling
Phone: +49 6221 42 1620
between insulin/IGF and TORC1 signaling via PRAS40
[email protected]
in Drosophila. Developmental Cell, 22, 172–182.
(3.) Hahn K. et al. (2010). PP2A regulatory subunit
PP2A-B’ counteracts S6K phosphorylation. Cell
Metabolism, 11, 438–444.
(4.) Francis V. et al. (2010). dDOR is an ecdysone receptor coactivator that forms a feed-forward loop connecting insulin and ecdysone signaling. Current
Biology, 20, 1799–1808.
Location of adipose tissue
in an adult fly revealed by
GFP expression.
72
Research Program
Structural and Functional Genomics
Molecular RNA Biology and Cancer
Helmholtz University Junior Research Group
Head: Dr. Sven Diederichs
A large fraction of the human genome is transcribed into RNA (more than 70%), while only
2% are protein-encoding. These recent insights
into RNA biology induced a paradigm shift towards the recognition of RNAs as functionally
important molecules – beyond serving as messengers for protein-encoding genes. Non-protein-coding RNAs execute important functions
in the cell. Short non-coding RNAs, the microRNAs, play important roles in gene regulation.
The tumor-suppressive or oncogenic role of
many microRNAs and their frequent deregulation in tumors allow a first glimpse of the
striking role that non-coding RNAs can play in
cancer. Novel long non-coding RNAs (ncRNA,
lncRNA, lincRNA) fulfill important functions
ranging from epigenetic gene regulation to
scaffolding functions in the cytoplasm. Taken
together, the human cell contains many more
RNAs than previously anticipated and many of
them might just await their discovery as functionally important molecules. Since cancer is
– in most cases – a disease of the genome, that
is caused by the deregulation of oncogenes
and tumor suppressor genes, we are convinced
that all parts of the human genome are important to study in tumor biology, not restricted
to the 2% protein-coding information.
Our research focuses on the new and innovative research area of long non-coding RNAs
and their role in cancer. We elucidate the expression patterns, regulatory mechanisms and
cellular and molecular functions of lncRNAs
relevant to cancer. The fascination as well as
the major challenge in lncRNA research is driven by the fact that each lncRNA can have a different function and a different mechanism, so
that many important discoveries and insights
into the molecular mechanisms underlying tumorigenesis can be expected from this field.
silence lncRNAs in cancer cells and RNA Affinity Purification to identify the interactomes of
cancer-associated lncRNAs. To further generate hypotheses on the lncRNA functions, we
use bioinformatic guilt-by-association studies.
To accelerate our discoveries of novel lncRNAs
in cancer, we have developed an siRNA library
specifically targeting 638 cancer-associated
lncRNAs identified in our screen and allowing
their rapid functional characterization.
One example nicely illustrates our research
approach: We identified the lncRNA MALAT1
(Metastasis-Associated in Lung Adenocarcinoma Transcript 1) as a biomarker associated
with a poor prognosis and the development of
distant metastasis in lung cancer (Oncogene
2003). We then developed a novel approach to
quantitatively silence this lncRNA in lung cancer cells by genome editing (Genome Res 2011).
This loss-of-function revealed that MALAT1 was
essential for cell migration and metastasis in
a xenograft mouse model. Joining forces with
ISIS Pharmaceuticals, we developed an inhibitor for MALAT1, an Antisense Oligonucleotide
(ASO), which effectively reduced MALAT1 in
the mouse model and suppressed lung cancer
metastasis (Cancer Res 2013). At the molecular
level, we identified MALAT1 as an epigenetic
regulator inducing a signature of metastasisassociated genes. In summary, MALAT1 can
serve as a biomarker and is an essential player
and promising therapeutic target for metastasis prevention in lung cancer.
ESSENTIAL PUBLICATIONS:
(1.) M Hämmerle M.* et al. (2013). Post-transcriptional
destabilization of the liver-specific long non-coding
RNA HULC by the IGF2 mRNA-binding protein 1 (IG-
Molecular RNA Biology and Cancer (B150)
German Cancer Research Center
Im Neuenheimer Feld 280
69120 Heidelberg
Phone: +49 6221 42 4380
[email protected]
The lncRNA MALAT1 is a marker for metastasis
development in lung cancer and associated with
poor survival (Oncogene 2003). Its suppression
using a novel silencing approach based on
genome editing (Genome Res 2011) prevents the
development of lung cancer metastasis in MALAT1KO cells (Cancer Res 2013).
F2BP1). Hepatology, 58, 1703–1712.
(2.) Liu M. et al. (2013) The IGF2-intronic miR-483 selectively enhances transcription from IGF fetal pro-
Future Outlook:
As a thriving research area, we analyze long
non-coding RNAs (lncRNA) and their role
in cancer. After profiling the expression of
thousands of lncRNAs in three tumor entities – lung, liver and breast cancer – we elucidate the cellular and molecular function
of lncRNAs regulated in cancer. Here, we use
innovative techniques like Genome Editing to
Research at DKFZ 2014
moters and enhances tumorigenesis. Genes Dev., in
press.
(3.) Gutschner T. et al. (2013). The non-coding RNA
MALAT1 is a critical regulator of the metastasis phenotype of lung cancer cells. Cancer Res., 73, 1180–1189.
(4.) Gutschner T. et al. (2011). Non-coding RNA gene silencing through genomic integration of RNA destabilizing elements using zinc finger nucleases. Genome
Res., 21, 1944–1954.
73
Structural and Functional Genomics
Systems Biology of Cell Death Mechanisms
Junior Research Group
Head: Dr. Nathan Brady
Systems Biology of Cell Death Mechanisms
(B170)
German Cancer Research Center
Im Neuenheimer Feld 280
69120 Heidelberg
Phone: +49 6221 54 51322
[email protected]
74
We are investigating the control and crosstalk
between programmed cell death (PCD) mechanisms of apoptosis, autophagy and necrosis in
pancreatic, breast and brain cancer cells. Apoptosis, the most studied PCD mode (Type I), is
activated by either the death receptor or the
mitochondrial pathway. Autophagy is a process by which intracellular components are
sequestered by autophagosomes, which then
fuse with and are degraded by lysosomes. In
the cancer cell autophagy can paradoxically
act as either an alternative cell death pathway
(Type II PCD) or as a potent survival response
to stress, e.g. hypoxia and chemotherapies. Although considered a passive cell death, many
pathways are common to necrosis and PCD
modes. In contrast to apoptosis, necrosis is inflammatory due to the rupture of the plasma
membrane and the release of specific cytosolic
components. As apoptosis does not generate an immune response, the strict focus on
apoptosis-inducing therapies may not be fully
productive.
Furure Outlook:
The group “Systems Biology of Cell Death
Mechanisms (B170)” is part of the SBCancer
network within the Helmholtz Alliance on
Systems Biology and is located in BioQuant,
Heidelberg University’s center for quantitative
biology. Furthermore the group is closely cooperating with the European Pancreas Center at
Heidelberg University Hospital headed by Prof.
Dr. Markus Wolfgang Büchler.
ESSENTIAL PUBLICATIONS:
(1.) Zhu Y. et al. (2013). Modulation of serines 17 and
24 in the LC3-interacting region of Bnip3 determines pro-survival mitophagy versus apoptosis. J Biol
Chem., 288, 1099–1113.
(2.)Hundeshagen P. et al. (2011). Concurrent detection
of autolysosome formation and lysosomal degradation by flow cytometry in a high-content screen for
inducers of autophagy. BMC Biol, 9, 38.
(3.) Wild P. et al. (2011). Phosphorylation of the Autophagy Receptor Optineurin Restricts Salmonella
Growth. Science. 333, 228–233.
(4.) Hamacher-Brady A. et al. (2011). Artesunate acti-
Our research is aimed at revealing how individual pathway activities and crosstalk between
PCD pathways can be tuned to optimize intrinsic and extrinsic pancreatic cancer cell death.
Using high-resolution imaging of high-content
biosensors we quantitatively map activities
and interdependencies of PCD modes. This approach achieves superior information content
than commonly reported population-averaged
and representative responses. Measured activities and dependencies, including proteinprotein interactions, inter and intra-organellar
communication, and bi-directional cell-to-cell
signaling are analyzed using computational
modeling approaches, with the aim of integrating qualitative and quantitative multi-parametric, multivariate datasets. Our overall goal
is to predict and test chemotherapies which
will optimize both initial PCD responses, as
well as promote an immunogenic response to
induce secondary killing of cancer cells by the
immune system.
Research Program
vates mitochondrial apoptosis in breast cancer cells
via iron-catalyzed lysosomal reactive oxygen species
production. J Biol Chem, 286, 6587–6601.
3D reconstruction of mitochondria (green),
lysosomes (red) and nuclei (grey). In response to
artesunate, lysosomes cluster asymmetrically at
the nucleus. Pro-death signaling from lysosomes
induces mitochondrial fragmentation and convert
mitochondria into inducers of cell death via
cytochrome c release.
Research at DKFZ 2014
75
Structural and Functional Genomics
Proteostasis in Neurodegenerative Disease
CHS Junior Research Group
(in Cooperation with Heidelberg University)
Head: Dr. Thomas Jahn
Proteostasis in Neurodegenerative Disease
(B180)
CHS Research Group at CellNetworks
Heidelberg University and DKFZ
German Cancer Research Center
Im Neuenheimer Feld 581
69120 Heidelberg
Phone: +49 6221 42-1551
[email protected]
One of the essential characteristics of living systems is the ability of their molecular
components to self-assemble into functional
structures and to balance their organisation
within the cellular environment through the
mechanism of homeostasis. It is clear that
protein homeostasis, or proteostasis, is closely
coupled to many other biological processes
ranging from the trafficking of molecules to
specific cellular locations to the regulation of
the growth and differentiation of cells. In addition, only correctly folded proteins have the
ability to remain soluble in crowded biological
environments and to interact selectively with
their natural partners. It is, therefore, not surprising that the failure of proteostasis mechanisms underpins the pathogenesis of common
diseases of old age, most notably, cancer and
neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease. In many such
diseases proteins self-assemble in an aberrant
manner into large molecular aggregates, including soluble oligomeric species and amyloid fibrils. Arguably, strategies to ameliorate
misfolding and aggregation will depend on a
detailed understanding of manipulators of the
proteostasis network.
Future Outlook:
The main interest of our lab is to advance
our understanding of the molecular events
triggered by protein misfolding and the subsequent impact of protein aggregation on cellular integrity. We combine biochemical and
molecular biological studies to tackle questions such as: What are the characteristics of
aggregated protein species accumulating in
vivo? How are specific species toxic to cells?
Which cellular mechanisms can be modified
to rescue proteostasis? To address these questions we combine protein engineering with
the wide range of genetic and molecular techniques available in cell culture and Drosophila
melanogaster. We are also very interested in
establishing novel experimental tools, which
include for example the quantitative analysis
of Drosophila models and the in vivo characterisation of protein-protein interactions.
Hopefully, understanding the detailed molecular processes leading to protein misfolding
will open new routes towards the design and
development of rational treatments for these
debilitating diseases.
ESSENTIAL PUBLICATIONS:
(1.) O’Sullivan et al. (2012). Reticulon-like-1, the Drosophila orthologue of the Hereditary Spastic Paraplegia gene reticulon 2, is required for organization of
endoplasmic reticulum and of distal motor axons.
Hum Mol Genet. 21, 3356–3365.
(2.) Jahn T.R. et al. (2011). Detection of Early Locomotor
Abnormalities in a Drosophila Model of Alzheimer’s
Disease by a Three-Dimensional Tracking System. J.
Neuroscience Methods. 197, 186–189.
(3.) Jahn T.R. et al. (2008). A common β-sheet archi-
Schematic energy landscape for
protein folding and aggregation
(see Jahn & Radford FEBS
J. 2005). The competition
between unimolecular folding
and aggregate formation is
intricately balanced by the cellular
proteostasis network.
tecture underlies in vitro and in vivo β2-microglobulin
amyloid fibrils. J. Biol. Chem., 283, 17279–17286.
(4.) Jahn T.R. et al. (2006). Amyloid formation under
physiological conditions proceeds via a native-like
folding intermediate. Nature Struct. Mol. Biol.,
13, 195–201.
This Junior Research Group is generously
supported by the Chica-and-Heinz-SchallerFoundation (CHS).
76
Research Program
Structural and Functional Genomics
Lysosomal Systems Biology
Junior Research Group
Head: Dr. Anne Hamacher-Brady
Programmed cell death (PCD) is regulated by
the spatially- and temporally- co-ordinated
interplay of genetically defined signaling pathways. The understanding of PCD is of central
importance, in that its successful execution is
the key to cancer therapy. As fundamental discoveries concerning PCD mechanisms, or even
new modes of PCD, are still being reported,
addressing the complexity of PCD signaling
is a growing challenge. Systems biology offers tools to utilize such biological complexity
through full data integration and mathematically-derived non-intuitive hypothesis generation. Intriguingly, PCD undergoes substantial
positive and negative regulation by the endolysosomal compartment.
logical modeling approaches, and are translating the achieved results to the organism level.
Primary goals are the systemic identification of
regulatory mechanisms governing lysosomal
and PCD signaling pathways and confirmation of in vivo functionality. Our research will
yield insights into specific mechanisms for optimizing cancer cell death. This junior research
group is funded by the Federal Ministry of Education and Research (BMBF).
ESSENTIAL PUBLICATIONS:
(1.) Zhai Z. et al. (2012). Antagonistic regulation of differentiation and apoptosis by the Cut transcription
factor represents a tumor suppressing mechanism in
Drosophila. PLoS Genet., 8(3):e1002582 .
(2.) Hamacher-Brady A. et al. (2011). Artesunate acti-
Future Outlook:
This junior research group is dedicated to the
elucidation of lysosomal control of PCD in cancer versus non-cancer cells, with an emphasis
on the cell culture experiments-based generation of theoretical model predictions, and testing of the in vivo-functionality in the model
organism C. elegans. To that end, we are integrating quantitative fluorescence microscopy
and biochemical methods with systems bio-
vates mitochondrial apoptosis in breast cancer cells
via iron-catalysed lysosomal reactive oxygen species
Lysosomal Systems Biology (B190)
production. J Biol Chem., 285,6587–6601.
BMBF e:Bio Junior Research Group
(3.) Hamacher-Brady A. et al. (2007). Response to my-
German Cancer Research Center
ocardial ischemia/reperfusion injury involves Bnip3
BIOQUANT
and autophagy. Cell Death Differ., 14, 146–157.
(4.) Hamacher-Brady A. et al. (2006). Enhancing mac-
Im Neuenheimer Feld 267
roauto-phagy protects against ischemia/reperfusion
69120 Heidelberg
injury in cardiac myocytes. J Biol Chem., 281, 29776–
Phone: +49 6221 54 51357
29787.
[email protected]
Metabolic stress-induced, E3 ligasemediated mitochondrial K63 ubiquitin
chaining in breast cancer cells. In this
image mitochondria are labeled in red, K63
ubiquitin chains in green, E3 ligase in blue.
Research at DKFZ 2014
77
Coordinator
Prof. Dr. Kari Hemminki
Cancer Risk Factors
and Prevention
About 210,000 people in Germany die of cancer each year. 470,000
new cancer cases are diagnosed yearly. Significant progress in prevention, diagnosis, and treatment of cancer has been made possible
through recent research results in the field of molecular biology.
Our research program is concerned with identifying risk factors
(primary prevention), early detection (screening), and approaches to
prevent disease progression (chemoprevention). The German Cancer
Research Center occupies a leading position in the area of epidemiological studies as well as in nutrition sciences, biostatistics, and the
application of biomarkers (characteristic biological features that are
key for the prognosis or diagnosis of cancer). We expect that it may
be possible to prevent up to 30 percent of new cancer cases within
the next 20 to 30 years. To reach this goal, the main activities of the
research program are focused on:
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78
integrating laboratory research, epidemiology, and clinical
studies
compiling and extending collections of biological samples and
databases
integrating genome, proteome, and biomarker research into
epidemiological and clinical studies on the causes and prevention of cancer
studies to identify causal connections such as between diet
and cancer
educational measures
research and quality control related to tests and early detection
programs
research in the fields of biostatistics and methodological consulting
Research Program
Research at DKFZ 2014
79
Cancer Risk Factors and Prevention
Epigenomics and Cancer Risk Factors
Division
Head: Prof. Dr. Christoph Plass
Epigenomics and Cancer Risk Factors (C010)
German Cancer Research Center
Im Neuenheimer Feld 280
69120 Heidelberg
Phone: +49 6221 42 3300
[email protected]
Aberrant DNA methylation is an early event
in tumorigenesis and a major contributor in
the development of solid tumors as well as
leukemias. As an epigenetic alteration, DNA
methylation does not change the sequence of
a gene and thus offers the exciting possibility for therapeutic removal of the methylation
group by demethylating drugs. Deregulation
of mechanisms that control the establishment
of normal DNA methylation patterns leads to
both extensive aberrant hypo- and hypermethylation and has been described for several human malignancies. Global DNA hypomethylation in human cancers was one of the earliest
changes associated with tumor progression.
Our group has shown that human malignancies are characterized by extensive promoter
CpG island methylation with non-random and
tumor-type specific patterns. It is currently
unknown how tumors acquire aberrant DNA
methylation patterns. Our division is interested in the molecular mechanisms underlying
the initiation and progression of malignant
cell growth. In particular, we are focusing our
attention on the contribution of epigenetic
alterations in this process and to determine
how epigenetic and genetic alterations cooperate during tumorigenesis. In our studies we are
utilizing current state-of-the-art high throughput epigenomic assays (e.g. Methylation arrays,
Next generation sequencing and MassARRAY) on clinical samples, cell culture models or
mouse tumor models.
Future Outlook:
Epigenetics is a fast evolving field with links to
many research directions in cancer research. A
challenge here will be to integrate epigenetic
questions with other data sets. For example,
the profiling of cancer genomes relied heavily
in the past on the description of genetic alterations. Now epigenetic datasets will need to be
integrated in order to completely understand
the molecular defects in cancer. Our division
will focus on four major research directions:
• Evaluation of genome-wide epigenetic
patterns in tumor genomes
• Identification of novel cancer genes and
pathways targeted by epigenetic alterations
• Determining the role of epigenetics in
cancer risk and progression
• Evaluate the role of epigenetics in the
regulation of DNA repair
ESSENTIAL PUBLICATIONS:
(1.) Raval A. et al. (2007). Downregulation of death-associated protein kinase 1 (DAPK1) in chronic lymphocytic leukemia. Cell, 129, 879–890.
(2.) Chen S.S. et al. (2009). Epigenetic changes during disease progression in a murine model of human
chronic lymphocytic leukemia. Proc. Natl. Acad. Sci.,
106, 13433–13438.
(3.) Plass C. et al. (2013). Mutations in regulators of
the epigenome and their connections to global chromatin patterns in cancer. Nat Rev Genet., 14, 765–780.
(4.) Wang Q. et al. (2013). Tagmentation-based wholegenome bisulfite sequencing. Nat Protoc., 8, 2022–
2032.
DAPK1 Mass Array
80
Research Program
Cancer Risk Factors and Prevention
Cancer Epidemiology
Division
Head: Prof. Dr. Rudolf Kaaks
Our division studies the causes of cancer in
population groups with the aim of identifying
and, if possible, avoiding risk factors so as to
prevent cancer. Our key focus is on the quantification of risks associated with lifestyle, nutrition and metabolism. In addition, we address
the question of how lifestyle may interact with
genetic susceptibility factors in cancer development.
ESSENTIAL PUBLICATIONS:
(1.) Hüsing A. et al. (2012), Prediction of breast cancer
risk by genetic risk factors, overall and by hormone
receptor status. J Med Genet. 49, 601–608.
(2.) Ritte R. et al. (2012). Adiposity, hormone replacement therapy use and breast cancer risk by age and
hormone receptor status: a large prospective cohort
study. Breast Cancer Res., 14, R76.
(3.) Grote V.A. et al. (2011). Diabetes mellitus, glycated
haemoglobin and C-peptide levels in relation to pan-
On the basis of established, genetic and nongenetic risk factors, we build quantitative risk
models for the identification of individuals
who have an increased risk of developing cancer compared to others, and who may have
increased benefit from targeted prevention
measures, such as regular cancer screening.
A further focus is exploring new routes for prevention and early diagnosis of cancer, as well
as quality control of introduced measures. Due
to the population-related approach, statistical
methods and their further development are of
particularly high relevance in epidemiology.
A major part of our research takes place within
the setting of large-scale prospective cohort
studies, such as the European Prospective Investigation into Cancer and Nutrition (EPIC),
and the Scandinavian Consortium of Maternity
Cohorts. For future studies, our division has a
central role in the development and set-up of
the “National Cohort” – a new, large-scale prospective cohort study in Germany.
Research at DKFZ 2014
creatic cancer risk: a study within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Diabetologia, 54, 3037–3046.
(4.) Campa D. et al. (2011). Genetic variability of the
mTOR pathway and prostate cancer risk in the European Prospective Investigation on Cancer (EPIC).
PLoS One, 6, e16914.
Cancer Epidemiology (C020)
German Cancer Research Center
Im Neuenheimer Feld 280
69120 Heidelberg
Phone: +49 6221 42 2200
Fax: +49 6221 42 2203
[email protected]
81
Cancer Risk Factors and Prevention
Molecular Genetic Epidemiology
Division
Head: Prof. Dr. Kari Hemminki
Molecular Genetic Epidemiology (C050)
German Cancer Research Center
Im Neuenheimer Feld 580
69120 Heidelberg
Phone: +49 6221 42 1800
[email protected]
Genome-wide association study
(Manhattan plot) on Hodgkin
lymphone (Enciso-Mora et al. Nature
Genet 2010). The strongest association
with many SNPs is shown for the MHC
complex on chromosome 6.
82
For common cancers, such as breast, prostate,
colorectal and lung cancers, familial risk for a
person who has an affected family member is
typically around 2.0; approximately 5 to 20%
of cases are familial when two generations
are considered. Known susceptibility genes
are estimated to explain some 15 to 30% of
the familial clustering of breast, prostate and
colorectal cancers but only about 1% of the
familial clustering of lung cancer. The recently
identified low-penetrance genes/loci explain
a large proportion of cancer occurrence (population-attributable fraction) but explain only
a small proportion of the known familial risks
for these cancers. This apparent paradox is explained by the high allele frequency of the loci
and the low conferred risk. However, the true
functional gene variants may be much rarer
and their contribution to familial risk would
be higher. For many relatively common cancers, such as bladder cancer and non-Hodgkin
lymphoma, only low-penetrance genes are
known, and they have negligible contribution
to the familial risk. Thus, there are large gaps
in knowledge on the genetic basis of familial
cancer that the Molecular Genetic Epidemiology division is addressing on two fronts. It is
using the world’s largest family dataset, the
Swedish Family-Cancer Database to assess
familial cluster in all cancers. It is characterizing gene underlying susceptibility to cancer
through genetic association studies, increasingly using genome-wide approaches.
relatives. In due course, the aim is to develop
software packages that would provide relative
and absolute risk estimates for a given family structure, age of onset of the diagnosed
cancers, presentation of related tumors and
other relevant data. There are several ongoing
genome-wide association studies, for example
on myeloma, Hodgkin disease, childhood leukemia, for which new low-penetrance genes
have been described. There is a future interest
to associate the findings with clinical parameters, such as survival and response to therapy.
Genome-wide association studies have been
conducted on breast cancer and melanoma
with a special reference to survival. In collaborative association studies on breast and
colorectal cancers genetics of cancer prognosis
and gene-environment interactions are under
focus.
ESSENTIAL PUBLICATIONS:
(1.) Prasad R. et al. (2010). Verification of the susceptibility loci on 7p12.2, 10q21.2 and 14q11.2 in childhood
precursor B-cell acute lymphoblastic leukemia. Blood,
15, 1765–1767.
(2.) Enciso-Mora V. et al. (2010). A genome-wide association study of Hodgkin Lymphoma identifies new
susceptibility loci at 2p16.1 (REL), 8q24.21, and 10p14
(GATA3). Nature Genet., 42, 1126–1130.
(3.) Hemminki K. et al. (2011). Familial risks in cancer
of unknown primary: tracking the primary sites. J Clin
Oncol., 29, 435–440.
(4.) Hemminki K. et al. (2011). Familial mortality and
familial incidence in cancer. J Clin Oncol., 29, 712–718.
Future Outlook:
The Swedish Family Cancer Database includes
increasingly older generations whereby case
numbers increase and it is possible to study
familial risks in rare and histology-specific
cancers. As one example, familial clustering
of cancer of unknown primary site is offering
interesting insights into metastatic phenotype. The database is being used to analyze
age-group-specific familial risks, which will be
turned into user-friendly algorithms for clinical
genetic counseling of cancer patients and their
Research Program
Cancer Risk Factors and Prevention
Biostatistics
Division
Head: Prof. Dr. Annette Kopp-Schneider
The main tasks of the Biostatistics Division are
service and research in the field of biostatistical methods and their application in cancer
research. We provide statistical support for all
scientific activities of the DKFZ from in vitro
and animal studies to human subject research
including clinical trial, linking methodical
research and biomedical disciplines. Our support covers experimental design, sample size
estimation, data analysis and preparation of
results for publication. It ranges from brief statistical consultations to long-term collaborations and covers standard statistical analysis
approaches as well as the development of
complex statistical methods tailored to specific questions. The ongoing evolution of novel
measurement techniques and platforms and
the development of new research questions
make it necessary to continuously refine the
biostatistical and biomathematical methodology and to develop and implement new methods for analysis. Our current research areas reflect the requests we are confronted with from
collaborators. We develop and assess efficient
and valid methods for visualizing, integrating
and analyzing data, in particular high-dimensional molecular data. We develop optimized
biometrical designs in experimental cancer research and in clinical studies. We devise methods of quantitative risk assessment.
Future Outlook:
One focus of interest of our research is the
evaluation of molecular data in biomarker
studies. We will extend our research to find
associations with clinico-pathological factors,
prognosis or response to therapy with the aim
to identify diagnostic, prognostic or predictive
factors. We will develop and validate statistical
methods for classification and prediction using
low- and high-dimensional data. The development of methods for data integration is becoming an important aspect of our work, e.g.
the development of Bayesian hierarchical models for classification and prediction, which can
make use of multiple data sources, while prop-
Research at DKFZ 2014
erly accounting for biological inter-relations
between these data. Another area of research
is the development and application of statistical and stochastic models for dose-response
relationships. In this context, we investigate
non-linear regression models. A special focus
lies on the description of cellular processes
using stochastic models to understand the
process of carcinogenesis or the effect of toxic
compounds on cell systems.
ESSENTIAL PUBLICATIONS:
(1.) Hielscher T. et al. (2010). On the prognostic value
of survival models with application to gene expression signatures. Statistics in Medicine, 29, 818–829.
(2.) Renner M.. et al. (2013). Stochastic time-concentration activity models for in vitro neurotoxicity.
Theor. Biol. Med. Model., 10, 19.
(3.) Weimer M. et al. (2012). The impact of data transformations on concentration-response modeling.
Toxicol.Lett., 213, 292–298.
(4.) Wunder C. et al. (2012). An adaptive group se-
Biostatistics (C060)
quential phase II design to compare treatments for
German Cancer Research Center
survival endpoints in rare patient entities. J. Biop-
Im Neuenheimer Feld 280
harm. Stat., 22, 294–311.
69120 Heidelberg
Phone: +49 6221 42 2391
[email protected]
The Principle of
Statistical Inference
83
Cancer Risk Factors and Prevention
Clinical Epidemiology and Aging Research
Division
Head: Prof. Dr. Hermann Brenner
Clinical Epidemiology and Aging Research
(C070)
German Cancer Research Center
Im Neuenheimer Feld 581
69120 Heidelberg
Phone: +49 6221 42 1301
[email protected]
The Clinical Epidemiology and Aging Research
Division’s main areas of research include
clinical cancer epidemiology, epidemiology of
chronic age-related diseases and epidemiological methods. In the field of clinical cancer
epidemiology, the group conducts large-scale
epidemiological studies on new avenues of
more effective cancer prevention and early
detection, and on issues of quality of medical
care, prognosis and quality of life of cancer
patients. Further large-scale epidemiological
studies focus on detection of risk factors, risk
markers and prognostic factors of cardiovascular disease, diabetes mellitus and arthritis,
thereby aiming to explore new avenues of enhanced prevention and management of these
common and strongly age-related diseases.
Most of the Division’s studies are conducted in
interdisciplinary, often international collaboration with cancer registries, clinical partners
and partners from the basic biological sciences. Apart from application of the highest
methodological standards in these studies, a
major area of research conducted in the Division is devoted to further development and
enhancement of methods in epidemiological
research.
Future Outlook:
The Division will expand its research on early
detection and screening for colorectal cancer
to focus on questions of high relevance to the
implementation of early detection programs
at the population level.
Future research in early detection and screening will also be directed towards other gastrointestinal cancers. Due to demographic aging,
along with steadily increasing cancer survival
rates, the number and prevalence of cancer
survivors in the population will continue to
increase. The Division will therefore intensify
its research on additional outcomes, such as
quality of life and the occupational and social
participation of cancer survivors. An area of
increasing interest in aging research will be
to enhance the empirical evidence for preventive and therapeutic interventions in old age.
Epidemiological aging research in the Division
will increasingly address integrative and functional endpoints that have received comparatively little attention thus far, such as indicators of multimorbidity and frailty, or indicators
of functional limitations, as these are often
more relevant for the elderly than single medical diagnoses. The Division will also contribute
its expertise in recruitment and follow-up of
population-based cohorts and in the areas
of clinical epidemiology, aging research and
epidemiological methods to the planning and
build-up of the National Cohort of 200,000
older adults to be recruited from 201 on and
followed over many years thereafter.
ESSENTIAL PUBLICATIONS:
(1.) Brenner H. et al. (2013). Colorectal cancer. Lancet.
doi: 10.1016/S0140-6736(13)61649-9. [Epub ahead of
print].
(2.) Brenner H. et al. (2012). Risk of colorectal cancer
after detection and removal of adenomas at colonoscopy: population-based case-control study. Journal of
Clinical Oncology, 30, 2969–2976.
Study assessing the potential
to enhance stool tests for early
detection of colorectal neoplasms.
The bold line indicates improved
detection of advanced adenomas by
immunochemical fecal occult blood
tests among men using low-dose
aspirin (Brenner et al, JAMA 2010).
(3.) Breitling L.P. et al. (2011). Tobacco smoking-related differential DNA methylation: 27k discovery and
replication. American Journal of Human Genetics, 88,
450–457.
(4.) Jansen L. et al. (2011). Health-related quality of life
over 10 years after diagnosis of colorectal cancer – a
population-based study. Journal of Clinical Oncology,
29, 3263–3269.
84
Research Program
Cancer Risk Factors and Prevention
Molecular Epidemiology
Research Group
Head: Prof. Dr. Barbara Burwinkel
One of the group’s main research interests in
the past five years has been the identification
of genetic and epigenetic risk factors for breast
and colorectal cancer. A special focus has been
on familial cancer, because genetic risk factors
are supposed to be enriched in this population and the power to detect risk variants
is enlarged in comparison to sporadic study
populations. After accepting the foundation
professorship at the Department of Obstetrics
and Gynaecology in 2008, the group’s research
interests have shifted to reveal molecular and
cellular factors (e.g. miRNA profiles, methylation signatures, genetic variants, mutations
and circulating tumor cells (CTCs)) associated
with prognosis and therapeutic response, as
well as to uncover molecular serum markers, as early detection markers for breast or
colorectal cancer and for the recurrence or
metastasis of breast and colorectal cancer. This
is done in cooperation with Hermann Brenner
and Jenny Chang-Claude (DACHS study), Jenny
Chang-Claude (MARIE study) and Andreas
Schneeweiß (University Womens Clinic and
NCT).
By developing peptide aptamers against ID
proteins, which are overexpressed in several
solid cancers including breast and ovarian
cancer and have been shown to be associated
with poor prognosis, the group is testing biomarkers as therapeutic targets. One peptide
aptamer against ID1 and ID3 that the group
has isolated has been shown to counteract the
oncogenic activities of ID1 and ID3 in vitro.
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•
•
•
and Claus Bartram from the Institute of
Human Genetics and the German Consortium of Hereditary Breast and Ovarian
Cancer (GC-HBOC). The group will also
evaluate the possibility of inherited epigenetic markers as cancer risk factors.
using methylation signatures, splice variants, mutations and miRNAs as prognostic and predictive markers and early detection markers.
identifying genetic germline variants that
alter therapeutic response.
detecting genetic germline variants affecting the target gene, its metabolizing
enzymes, and proteins involved in drug
absorption, transport, metabolism and
excretion that might be associated with
therapeutic response. This project will be
done in cooperation with Andreas Schneeweiß and Frederik Marmé (University Womens Clinic and NCT).
performing the molecular characterization of circulating cancer (stem) cells. The
group has started a collaboration with
Andreas Schneeweiß (University Womens Clinic, Heidelberg, and NCT), Andreas
Trumpp (Division Stem Cells and Cancer, A010) and has built up a metastatic
breast cancer study (MBSUCH).
ESSENTIAL PUBLICATIONS:
(1.) Ghoussaini M. et al. (2012). Identification of three
new loci associated with breast cancer susceptibility.
Nat Genet. 44, 312–318.
Molecular Epidemiology (C080)
German Cancer Research Center
Im Neuenheimer Feld 581
69120 Heidelberg
Phone: +49 6221 42 1461
[email protected]
12p12.3 deletion identified in two familial CRC
cases using Affymetrix SNP 6.0 array (x axis: logR
intensity ratio, blue bars; y axis: B allele frequency,
red circles). Deletion regions are in black boxes.
(2.) Wirtenberger M. et al. (2006). Identification of
Future Outlook:
The major aims of the group are:
• identifying rare intermediate and high
breast cancer risk variants that might
contribute more to familial cancer risk
than previously assumed via capture
techniques and next-generation sequencing methods, combined with the well
characterized familial breast cancer study
population collected by Christian Sutter
Research at DKFZ 2014
frequent chromosome copy-number polymorphisms
by use of high-resolution single-nucleotide-polymorphism arrays. Am J Hum Genet., 78, 520–522.
(3.) Frank B. et al. (2008). Association of a common
AKAP9 variant with breast cancer risk: a collaborative
analysis. J Natl Cancer Inst, 100, 437–442.
(4.) Stein S. et al. (2010). Genomic Instability and Myelodysplasia with Monosomy 7 Consequent to EVI1 Activation after Gene Therapy for Chronic Granulomatous Disease. Nat Med., 16, 198–204.
85
Coordinator
Prof. Dr. Hans-Reimer Rodewald
Tumor Immunology
The immune system is our body’s most powerful weapon to combat
pathogens and cancer cells. However, tumor cells have a repertoire of tricks to evade the immune response. The divisions of the
Research Program Tumor Immunology investigate the mechanisms
regulating the behavior of immune cells. Research work focuses on
cell proliferation and programmed cell death (apoptosis) as well as
on the activation and regulation of immune cells. Also under investigation are cancers affecting the immune system as such. The aim
is to better understand the role of the immune system in cancer,
AIDS, and autoimmune diseases. The findings will be translated into
new approaches for clinical application to utilize the potential of
the immune system for fighting cancer.
86
Research Program
Research at DKFZ 2014
87
Tumor Immunology
Translational Immunology
Division
Head: Prof. Dr. Philipp Beckhove
Translational Immunology (D015)
German Cancer Research Center and NCT
Im Neuenheimer Feld 460
69120 Heidelberg
Phone: +49 6221 56 5466
[email protected]
The immune system is characterized by its capability to recognize and eliminate malignant
tumors. Immunotherapies exploit this unique
ability and promise to become an efficient
complement to standard tumor treatments
in the future. The objective of the division
“Translational Immunology" is to gain new
insights into the immune defence system of
cancerous cells and to evolve the results from
basic research through to clinical treatments.
The pursuit of this is based on close interdisciplinary collaboration with the oncological
departments of the university hospital. New
therapeutic concepts developed by the division
are being “translated” into clinical application
under the auspices of the National Center for
Tumor Diseases (NCT) Heidelberg. Effective
immune responses are based on a variety of
active principles. The division is looking for options to draw on the immune system´s functions as a complementary treatment in the
battle against cancer within the framework
of synergystic projects. The project “T Cell Tumor Immunity” (Prof. Dr. Beckhove) describes
formative and regulative mechanisms of T cell
tumor responses. The project group “Tumorantigens” (Prof. Dr. Eichmüller) investigates the
immunogenicity of tumor-associated antigens
and develops strategies for tumor-specific immunization using preclinical model systems.
their clinical application (project “Antibody
Therapy", Dr. Moldenhauer). The role cell adhesion molecules play as target structures for immunotherapies related to metastasis and their
role during tumor metastasis are the central
topics of the project “Adhesion and Metastasis" (Prof. Altevogt). Particular glycosylation
patterns on tumor cells and tumor vessels are
not only decisive preconditions of tumor angiogenesis and tumor progression, but they
also represent ideal target antigens for new
anti-tumor strategies via mimetics with analogue structure and glycan-specific cytotoxic
antibodies (project “Glycoimmunology" , PD Dr.
Schwarz-Albiez).
ESSENTIAL PUBLICATIONS:
(1.) Ge Y. et al. (2012). Metronomic cyclophosphamide
treatment in metastasized breast cancer patients:
immunological effects and clinical outcome. Cancer
Immunol Immunother. 61, 353–362.
(2.) Bonertz A. et al. (2009). Antigen-specific Tregs
control T cell responses against a limited repertoire
of tumor antigens in patients with colorectal carcinoma. J Clin Invest. 11, 3311–3321.
(3.) Domschke C. et al. (2009). Intratumoral cytokines
and tumor cell biology determine spontaneous
breast cancer-specific immune responses and their
correlation to prognosis. Cancer Research. 21, 8420–
8428.
(4.) Beckhove P. et al. (2004). Specifically activat-
Future Outlook:
The examination of conditions and activation
of tumorlytic T and NK lymphocytes are the
focus of the project “Antigen Presentation and
T Cell Activation" (PD Dr. Momburg). Both projects are complemented by the construction
of virus-like particles (VLP) aimed to stimulate
immune responses against cancer (project
“VLP" , Dr. Cid). In the past decade, monoclonal
antibodies, either on their own or in combination with chemotherapy, have proven to be an
effective therapeutic agent in the treatment
of different tumor diseases. New therapeutic
antibodies are being developed with the help
of antibody engineering and tested before
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Research Program
ed CD45R0+ central and effector memory but not
CD45RA+ naïve T cells from bone marrow of cancer
patients selectively home to and reject xenotransplanted autologous tumors. J. Clin. Invest. 114, 67–76.
Tumor Immunology
Immunogenetics
Division
Head: Prof. Dr. Peter Krammer
The division of Immunogenetics has made
several groundbreaking contributions to the
field of programmed cell death (apoptosis).
The group established that the CD95 receptor does not only act as a death receptor that
induces apoptosis, but also triggers the NF-kB
pathway involved in tumor proliferation, invasion and metastasis. Together with APOGENIX,
a company founded with DKFZ, the group has
developed the biological APG101, a soluble fusion protein consisting of two extracellular
domains of the CD95 receptor and an antibody
Fc fragment (CD95-Fc). APG101 has therapeutic
effects in many diseases, e.g. in cancer.
Two TCM anti-cancer compounds, Wogonin
and Rocaglamide could be shown to preferentially induce apoptosis in tumor cells. The cyclin-dependent kinase 9 (CDK9) was identified
as the direct molecular target of Wogonin, and
Prohibitin 1 and 2 were identified as the target
of Rocaglamide. These studies point to the potential use of these compounds as an adjuvant
for anti-cancer therapy. Annexins were shown
to be involved in induction of peripheral tolerance against antigens from apoptotic cells.
Members of the annexins protein family are
transferred early upon induction of cell death
to the surface of apoptotic cells. By inhibition
of NF-κB signaling, annexins suppress dendritic cell (DC) maturation.
Finally, a redox-regulating molecule, AF-1, was
identified that is associated with aging of human cells. Knock down of AF-1 can also substantially extend stress resistance and life span
in drosophila. AF-1 seems to be involved in a
general aging mechanism.
mechanisms of novel NF-κB regulating phosphatases will be characterized. Since the enzymes identified influence cell death of tumor
cells, the ultimate goal is to find ways to manipulate them to treat patients. Annexins on
the surface of apoptotic tumor cells suppress
the anti-tumor immune response. Therefore,
manipulation of the annexin system promises
benefits for tumor therapy. The group will focus on the identification of the annexin receptor and the molecular mechanism by which
annexin treatment inhibits proinflammatory
signaling. Future directions of the group´s
work in redox regulation will involve the investigation of the role of AF-1 as a putative master
switch in aging. Here, the focus of the division
will be on AF-1´s molecular mechanism, its
drugability, and its role in age-related diseases.
ESSENTIAL PUBLICATIONS:
(1.) Kamiński M.M. et al. (2012). T cell activation is driven by an ADP-dependent glucokinase linking en-
Immunogenetics (D030)
hanced glycolysis with mitochondrial reactive oxy-
German Cancer Research Center
gen species generation. Cell Rep., 2, 1300–1315.
(2.) Brechmann M. et al. (2012). A PP4 holoenzyme
Im Neuenheimer Feld 280
balances physiological and oncogenic nuclear fac-
69120 Heidelberg
tor-kappa B signaling in T lymphocytes. Immunity. 37,
Phone: +49 6221 42 3718
697–708.
(3.) Kiessling M.K. et al. (2011). High-throughput mu-
[email protected]
tation profiling of CTCL samples reveals KRAS and
NRAS mutations sensitizing tumors toward inhibition of the RAS/RAF/MEK signaling cascade. Blood.
117, 2433–2440.
(4.) Schleich K. et al. (2012). Stoichiometry of the CD95
death-inducing signaling complex: experimental and
modeling evidence for a death effector domain chain
model. Mol Cell. 47, 306–319.
Future Outlook:
Future work will be directed at trying to block
the CD95 death pathway. In addition, CD95
mediated non-death pathways will be addressed by two approaches: resensitization
towards apoptosis by drugs, and blocking
of CD95 receptor signaling by drugs and/or
soluble CD95 receptors. Further trials with the
soluble CD95 receptor APG101 are currently
planned. The binding of Wogonin and Rocaglamide to their targets will be elucidated at the
atomic level. The insight into these molecular
interactions will serve as a platform for further
drug screening. Furthermore, the molecular
Research at DKFZ 2014
CD95 signaling: A death inducing signaling complex
(DISC) assembles upon binding of the CD95 ligand
(CD95L) to its receptor CD95. The proteins FADD,
procaspases-8/10 and c-FLIP have been shown to
be key components of this structure (for details
see Krammer et al. 2007, Nat Rev Immunol). The
signal can either lead to cell death (apoptosis) or to
proliferation and invasion.
89
Tumor Immunology
Molecular Immunology
Division
Head: Prof. Dr. Bernd Arnold
The Division of Molecular Immunology investigates basic mechanisms that are important for
immunological tumor rejection with the aim
to exploit this knowledge for the development
of novel immunotherapeutic strategies. Our research groups focus on the following topics:
Molecular Immunology (D050)
German Cancer Research Center
Im Neuenheimer Feld 280
69120 Heidelberg
Phone: +49 6221 42 3731
[email protected]
Antigen presentation: For successful destruction of tumor cells T lymphocytes need to be
activated by dendritic cells presenting tumor
antigens. Therefore, we are studying homeostasis and stimulatory capacity of dendritic cells, and measure the precise biophysical interaction forces between antigen-presenting
cells and T cells.
Peripheral tolerance: T lymphocytes are often
rendered tolerant by tumors and, therefore, fail
to attack the tumor. By investigating the molecular pathways leading to tolerance induction we identified a novel immune-modulator,
Dickkopf-3, that can down-regulate T cell responses and may represent a novel tumor escape mechanism.
Tumor microenvironment: The tumor vasculature can restrict the access of T lymphocytes into the tumor, thereby preventing tumor eradication. We succeeded in strongly
improving infiltration and tumor rejection by
strategies that modulate the tumor microenvironment, including local irradiation, efficient
depletion of regulatory T cells, and targeting of
vasculature-associated genes. These strategies
will be translated into the clinic.
Future Outlook:
We investigate basic mechanisms that are crucial for immunological tumor rejection. We are
focusing on the following aims:
Peripheral tolerance: Tissues particularly sensitive to inflammatory damage, like the brain
and the eye, create an immune-suppressive
microenvironment to limit immune responses. Likewise, developing tumors can generate a
tolerogenic milieu, which facilitates tumor progression and antagonizes the efficacy of vaccination strategies. Our understanding of the
key cellular and molecular players responsible for the induction and maintenance of tolerance is yet to be completed. Therefore, we
will address the molecular basis of immune silencing by healthy organs and tumor cells and
will focus on the identification of new molecular targets suitable for therapeutic reprogramming of the immune system.
Tumor microenvironment: Normalization of
the tumor vasculature is likely to play a major
role in T cell infiltration, which is a prerequisite
for tumor rejection. Therefore, we will analyze
the cellular and molecular mechanisms resulting in modulation of the tumor microenvironment, vessel normalization, and T cell infiltration. In particular, we will focus on regulatory
T cells and polarized macrophages that shape
the tumor microenvironment (in collaboration
with P. Beckhove). Identification of factors enhancing T cell infiltration will have important
implications for clinical immunotherapy.
ESSENTIAL PUBLICATIONS:
(1.) Papatriantafyllou M. et al. (2012). Dickkopf-3, an
immune-modulator in peripheral CD8 T cell tolerance. Proc Natl Acad Sci USA, 109, 1631–1636.
(2.) Hamzah J. et al. (2008). Vascular normalization in
RGS5-deficient tumors promotes immune destruction. Nature, 453, 410–414.
(3.) Hochweller K. et al. (2010). Dendritic cells control
T cell tonic signalling required for responsiveness to
We identified Dickkopf 3 as a novel immune
modulator which is mainly expressed in
tissues termed immune-privileged, such as
brain and eye. It dampens T cell reactivity in
such tissues protecting them against immune
destruction. Here the expression of Dickkopf 3
is shown in neurons in the mouse brain.
90
Research Program
foreign antigen. Proc. Natl. Acad. Sci., 107, 5931–5936.
(4.) Klug F. et al. (2013) Low-dose irradiation programs
macrophage differentiation to an iNOS+/M1 phenotype that orchestrates effective T cell immunotherapy. Cancer Cell, doi: 10.1016/j.ccr.2013.09.014 (epub
ahead of print).
Tumor Immunology
Developmental Immunology
Division
Head: Prof. Dr. Bruno Kyewski
selection of promiscuously expressed genes in
mTECs at the single cell and population level.
We expect the different and complementing
avenues of inquiry to provide us with a more
comprehensive understanding of the functional organization of the thymic- microenvironment in the context of self-tolerance, and
new insights into gene (co)-regulation in case
of pGE and beyond. In addition, we will continue to directly apply our findings in basic research to human disorders, i.e. further explore
the interrelationship between pitfalls of pGE
and human autoimmune diseases and identify
underlying molecular mechanisms controlling the intra-thymic expression of prominent
auto-antigens. In the context of pGE, we also
study the developmental biology of thymic
epithelial cells, with the future aim to follow
their full course of differentiation in vitro and
in vivo from the tissue-resident bi-potent stem
cell to the terminally differentiated stage. This
topic entails the identification and characterization of TEC stem cells and the development
of appropriate in vitro culture.
Finally, we will exploit our acquired knowledge
on the biology of human thymic epithelial cells
to develop new diagnostic tools for human
thymoma subtypes.
Developmental Immunology (D090)
German Cancer Research Center
Im Neuenheimer Feld 280
69120 Heidelberg
Phone: +49 6221 42 3734
[email protected]
A
ESSENTIAL PUBLICATIONS:
capsule
(1.) Derbinski J. et al. (2001). Promiscuous gene expression in medullary thymic epithelial cells mirrors the
peripheral self. Nat. Immunol., 2, 1032–1039.
cortex
Self/non-self discrimination is a hallmark of
the immune system of multi-cellular organisms. The thymus of higher vertebrates plays a
central role in the induction of T cell tolerance
(“central tolerance”). During self-tolerance
induction, the highly diverse T cell receptor
repertoire is probed against an unknown array
of self-antigens mirroring the “immunological
self” of the body. These interactions rid the repertoire of auto-reactive T cells. Our discovery
of promiscuous gene expression (pGE) and its
essential function in preventing organ-specific
autoimmunity has led to a reappraisal of the
role of central tolerance in self/non-self discrimination. The diversity of self-ligands in the
thymus is to a large extent generated by ectopic or promiscuous expression of numerous
tissue-restricted antigens in medullary thymic
epithelial cells (mTECs). This gene pool encompasses > 25 % of all known genes and represents virtually all tissues of the body. Promiscuous gene expression allows self-antigens,
which otherwise are expressed in a spatially or
temporally restricted manner, to become continuously accessible to developing T cells thus
rendering them tolerant. Specific failure of promiscuous gene expression can lead to severe
organ-specific autoimmune diseases like type 1
diabetes mellitus. This gene pool also includes
tumor-associated antigens, thus imposing immunological tolerance towards tumors, a fact
to be considered in the selection of tumor antigens for clinical vaccination trials.
cortical
epithelial cell
(2.) Kyewski B. and Klein L. (2006). A central role for
Research at DKFZ 2014
central tolerance. Annu. Rev. Immunol., 24, 571–606.
thymocyte
(3.) Lv H. et al. (2011). Impaired thymic tolerance to al-
macrophage
pha-myosin directs autoimmunity to the heart in
mice and humans. J. Clin. Invest., 121, 1561–1573.
(4.) Pinto S. et al. (2013). Overlapping gene coexpression patterns in human medullary thymic epithelial
cells generate self-antigen diversity. Proc. Natl. Acad.
Sci. 110, E3497–E3505.
trabecule
medulla
Future Outlook:
PGE represents one of the most fascinating
and arcane aspects of T cell tolerance. In future
we will further pursue our studies on the cellular and molecular regulation of this phenomenon in experimental in vitro and in vivo models. In particular, we would like to understand
how a terminally differentiated epithelial cell
type generates such a diverse self-antigen
repertoire in a mosaic fashion, such that the
expression patterns of individual mTECs faithfully add up to the full complement of selfantigens at the population level. In this context we will search for rules which guide the
subcapsular
epithelial cell
medullary
epithelial cell (mTEC)
B-cell
dendritic cell
The thymus is the site where central T cell
tolerance is imposed. It consists of an outer cortex
and a central medulla. The medulla is densely
packed with various antigen-presenting cells,
which present a plethora of self-antigens to
developing T cells and thus induce self-tolerance.
Medullary thymic epithelial cells (shown in red)
have the unique property to express numerous
tissue-restricted self-antigens in a promiscuous
fashion and thus are essential for the prevention of
autoimmunity.
91
Tumor Immunology
Cellular Immunology
Division
Head: Prof. Dr. Hans-Reimer Rodewald
Cellular Immunology (D110)
German Cancer Research Center
Im Neuenheimer Feld 280
69120 Heidelberg
Phone: +49 6221 42 4120
[email protected]
The Division of Cellular Immunology is investigating physiological and pathological processes of the development of cells and organs
in the immune system as well as their immunological functions.
We generated reporter knockin mice to demonstrate that T cells and myeloid cells (e.g.
dendritic cells and granulocytes) arise in the
thymus from distinct progenitors under physiological conditions. Moreover, a genetic block
of Notch1 signals in T cell progenitors leads
to their developmental deviation to dendritic
cells instead of T cells. T cell development and
maturation occur in a discrete primary immunological organ, the thymus. Previous projects
focussed on thymus organogenesis while
in current projects we investigate functions
of the transcription factor FoxN1 in thymic
epithelial cells (TECs). A central area of our research is the investigation of the roles of mast
cells in the immune system. Different knockout mice enabled us to characterize an enzyme
of the heparin biosynthesis pathway and to
elucidate the mechanism by which mast cell
proteases can degrade endothelin, a blood
pressure regulating factor, and detoxify structurally related snake toxins.
origins of different tissue resident macrophages like osteoclasts, Kupffer cells in the liver, and
microglia in the central nervous system. We
are extending our thymus research towards
unravelling mechanisms of acute T cell leukaemia (T-ALL) development. We discovered that
thymocytes undergo transformation if they
non-physiologically persist in the thymus. This
occurs with surprisingly high incidence if the
influx of fresh progenitors into the thymus is
interrupted. We hope that this new T-ALL model shall enable us to investigate the cellular
and molecular mechanisms of T-ALL formation
in the thymus. Comprehensive investigations
of mast cell functions remain a central area of
our research. We have generated a mouse mutant, which is completely mast cell deficient
but has an otherwise normal immune system.
This new mouse represents an excellent model
to clarify the question in which infections or
diseases beyond allergy mast cells play immunological roles. Specifically, we will test the
roles of mast cells in wound healing, asthma,
responses to infections and in tumour models.
ESSENTIAL PUBLICATIONS:
(1.) Schlenner S.M. et al. (2010). Fate mapping reveals
separate origins of T cells and myeloid lineages in the
Future Outlook:
Members of our team study the dynamic processes of stem cell differentiation and the plasticity of the development of mature immune
cells. To this end, we develop mouse models in
which stem cells and their progeny are inducibly labelled at a certain time point. Furthermore, we have generated ‘universal stem cell
recipient’ mice which can be transplanted with
bone marrow stem cells without the need for
myeloablation, e.g. by irradiation. In another
fate mapping project we are investigating the
Immunfluorescence staining of lymphocytes (red) and
osteoclasts (green) in bone marrow of a mouse femur.
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Research Program
thymus. Immunity, 32, 426–436.
(2.) Martins VC et al. (2012). Thymus-autonomous T
cell development in the absence of progenitor import. J Exp Med, 209, 1409–1417.
(3.) Feyerabend T.B. et al. (2011). Cre-Mediated Cell Ablation Contests Mast Cell Contribution in Models of
Antibody- and T Cell-Mediated Autoimmunity.
Immunity, 35, 832–844.
(4.) Rodewald H.R. et al. (2012). Widespread immunological functions of mast cells: fact or fiction?
Immunity, 37, 13–24.
Tumor Immunology
Innate Immunity
Boveri Junior Research Group
Head: PD Dr. Adelheid Cerwenka
The innate immune response serves as the
first line of immune defence and does not only
directly lead to tumor cell destruction, but
also to efficient subsequent activation of the
adaptive immune system. The Boveri Junior
Group “Innate Immunity" investigates Natural Killer (NK) cells and myeloid cell subsets
in cancer with the goal to improve therapeutic anti-tumor strategies. NK cells potently
kill tumor cells and produce inflammatory
cytokines. Their activation is determined by a
delicate balance between signals delivered by
inhibitory receptors, most of which are specific
for self-MHC class I, and activating receptors.
Many tumors lose expression of MHC class I
molecules and frequently escape from direct
recognition by CD8+ T cells, but become highly
susceptible to NK cell-mediated killing. Thus,
we believe that it is of major importance to
explore NK cell-based therapies against cancer.
Our research focuses on three strategies to
amplify innate immune cell-mediated antitumor responses. 1.) It is our goal to guide high
numbers of highly active, persistent NK cells
to the tumor site. 2.) We attempt to increase
the visibility of tumor cells to NK cells by the
upregulation of ligands for activating NK cell
receptors on tumors. 3.) We aim at exploring
inflammatory pathways in myeloid cells and
their functional importance in the context of
cancer.
Future Outlook:
Our future projects will further continue to
develop strategies aiming at harnessing NK
cells against tumors. In addition, candidates in
inflammatory signalling pathways in myeloid
cells and their functional importance in the
context of cancer inflammation will be investigated. Our overall program is designed to gain
novel insight in mouse and human NK cell and
myeloid cell biology building the basis for innovative strategies of immunotherapy against
cancer.
ESSENTIAL PUBLICATIONS:
(1.) Cerwenka A., Lanier LL. (2001). NK cells, viruses and
cancer. Nature Immunol. Rev., 1, 41–49.
(2.) Schlecker E. et al. (2012). Tumor-infiltrating monocytic myeloid-derived suppressor cells mediate CCR5dependent recruitment of regulatory T cells favouring tumor growth. J.Immunol., 189, 5602–5611.
(3.) Ni J. et al. (2012). Sustained effector function of IL12/15/18 preactivated NK cells against established tu-
Innate Immunity (D080)
German Cancer Research Center
mors. J Exp Med, 209, 2351–2365.
Im Neuenheimer Feld 280
(4.) Fiegler N. et al. (2013). Downregulation of the ac-
69120 Heidelberg
tivating NKp30 ligand B7-H6 by HDAC inhibitors impairs tumor cell recognition by NK cells. Blood, (epub
ahead of print).
Phone: +49 6221 42 4480
[email protected]
CD56-positive NK cells (brown)
infiltrating cervical carcinoma.
Research at DKFZ 2014
93
Tumor Immunology
Immune Tolerance
Helmholtz University Junior Research Group
Head: Dr. Markus Feuerer
Immune Tolerance (D100)
German Cancer Research Center
Im Neuenheimer Feld 280
69120 Heidelberg
Phone: +49 6221 42 1530
[email protected]
The immune system has evolved over time to
defeat external threats such as bacteria and
viruses as well as internal threats like cancer.
The ability of the immune system to destroy
such a diverse number of foreign invaders is a
tribute to its flexibility. However, this comes at
a price and the complexity can lead to severe
autoimmune diseases. In addition, misguided or deregulated immune responses have
recently been implicated in non-classical immune disorders such as obesity. To minimize
such collateral damage, powerful mechanisms
of immune tolerance have evolved to keep
unwanted immune responses at bay. These
mechanisms must be tightly controlled as
overactive immune tolerance can specifically
counteract desirable immune reactions (e.g.
anti-tumor or anti-microbial). Peripheral immune regulation is maintained by specialized
cells, including T cells and myeloid-derived
cells. The ability to actively suppress an immune response makes regulatory T (Treg) cells
important elements to consider. Treg cells are
a specialized lineage of CD4+ T cells, characterized by expression of the transcriptional
regulator Foxp3. Treg cells are essential for the
maintenance of self-tolerance.
Our goal is to explore Treg cell biology in the
context of autoimmunity and anti-tumor-immunity. What are the molecules behind these
specialized cells? In addition, we are interested
in how the local microenvironment shapes the
function of Treg cells.
ways that control the development and function of Foxp3+ Treg cells.
Peripheral immune regulation is not only
maintained by adoptive immune cells but also
by innate cells such as myeloid cells.
As a second main project, we are focusing
on understanding the role that myeloid cells
play in immune regulation. Myeloid cells are a
heterogeneous group of cells involved at the
interface of inflammation and wound-healing. Some members promote inflammation
whereas others have suppressive or regulatory functions. We are especially interested
in investigating how monocytes and their
progenies (– for example, tumor-associated
macrophages) can contribute to inflammation
or productive immunity on one hand and tolerance or tissue repair on the other. What is their
relationship to inflammation that promotes
cancer formation or progression?
ESSENTIAL PUBLICATIONS:
(1.) Hettinger J. et al. (2013). Origin of monocytes and
macrophages from a committed progenitor. Nature
Immunology, 14, 821-830.
(2.) Feuerer M. et al. (2009). How punctual ablation of
Foxp3+ T cells unleashes an autoimmune lesion within the pancreas islets. Immunity, 31, 654–664.
(3.) Feuerer M. et al. (2009). Lean, but not obese, fat
is enriched for a unique population of regulatory T
cells that affect metabolic parameters. Nature Medicine,15, 930–939.
(4.) Feuerer M. et al. (2001). Therapy of human tumors in NOD/SCID mice with patient-derived reac-
Future Outlook:
Harnessing the potential of Treg cells is one
of the most promising new immune system
based approaches to control immune function
and treat autoimmune diseases and cancer.
However, future strategies to bring Treg-based
therapies into clinical application will rely on
a better understanding of the molecular path-
Immune cells infiltrate and destroy
pancreatic insulin producing islet cells.
94
Research Program
tivated memory T cells from bone marrow. Nature
Medicine, 7, 452–458.
Structural and Functiona Genomics
Applied Tumor-Immunity
Clinical Cooperation Unit
Head: Prof. Dr. Dirk Jäger
In 2013, Dirk Jäger became head of the Clinical
Collaboration Unit “Applied Tumor Immunity”
at DKFZ. His research team focuses on the development of advanced analytical methods to
characterize tumor host interactions in the immunological tumor microenvironment and the
periphery. In particular whole-slide imaging of
histological sections coupled with automatic
image processing, laser microdissection and
multiplex protein quantification technologies
as well as multiplex serological assays have
been established. The goal is a comprehensive
mechanistic analysis of immunological pathomechanisms in the tumor microenvironment
and to develop individualized immunological
therapy approaches that are then translated
into clinical care of individual patients. These
insights have led to a successful phase I clinical trial (NCT00001) that can be seen as the
blueprint for individualized immunological
approaches. As the department of medical oncology is the main unit for cancer patient care
at the NCT, the direct link between research in
the Clinical Cooperation Unit and translation
into clinical trials and care is highly efficient.
will improve our understanding of cancer at
different levels. In a recently funded project by
the Heidelberg Center for Personalized Oncology (HIPO), we aim at revealing the mutational
landscape of colorectal cancer liver metastases
and the immunological specificities of infiltrating immune cells. Bioinformatical epitope
predictions complement this analysis and will
identify novel immunotherapeutic targets,
which can then be evaluated in vitro and prospectively in early clinical trials.
ESSENTIAL PUBLICATIONS:
(1.) Klug F. et al. (2013). Low-Dose Irradiation Programs
Macrophage Differentiation to an iNOS(+)/M1 Phenotype that Orchestrates Effective T Cell Immunotherapy. Cancer Cell. 24, 589–602.
(2.) Halama N. et al. (2011). Localization and density of
immune cells in the invasive margin of human colorectal cancer liver metastases are prognostic for response to chemotherapy. Cancer Res. 71, 5670–5677.
(3.) Halama N. et al. (2011). Natural Killer Cells are
German Cancer Research Center
Scarce in Colorectal Carcinoma Tissue Despite High
Im Neuenheimer Feld 460
Levels of Chemokines and Cytokines. Clin Cancer Res,
69120 Heidelberg
17, 678–689.
(4.) Gnjatic S. et al. (2010). Seromic profiling of ovari-
Future Outlook:
The future goal of this Clinical Cooperation
Unit is to develop and apply powerful tools to
better stratify patients, analyze the microenvironment, and offer tailored treatments for
individual patients. The further development
of advanced technologies will allow an unparalleled insight into the makeup of the immunological pathomechanisms in serum samples,
archival and fresh cancer specimens, as well as
in new non-rodent explant models from patients. Extending immunological data sets by
analyzing the mutational repertoire of tumors
Applied Tumor-Immunity (D120)
Phone: +49 6221 56 7228
an and pancreatic cancer. Proc Natl Acad Sci U S A, 107,
[email protected]
5088–5093.
and Director of the Medical Oncology, NCT
CD3 positive T cells
(brown) at the invasive
margin of a Colorectal
Cancer Liver Metastasis.
Research at DKFZ 2014
95
Coordinator
Prof. Dr. Heinz-Peter Schlemmer
Imaging and
Radiooncology
It is the task of the Research Program “Imaging and Radiooncology"
to introduce new findings, methods, and technologies into the diagnosis and treatment of cancer. Our goal is to detect early and comprehensively understand the specific tumor biology and to tailor radiooncologic treatment to the individual patient for improving cure
rates and quality of life. Knowledge gained from basic research in
the fields of imaging, radiation physics, engineering, radiopharmacy,
as well as radiation- and tumor biology are translated in systematic
preclinical and clinical studies and finally applied in clinical studies
for improving diagnostic and therapeutic strategies. The multidisciplinary Research Program is centred around the development and
implementation of imaging and radiotherapy technology, which
is achieved through intensive collaboration between the fundamental research divisions of the Research Program and the Clinical
Cooperation Units. Based on the complexity of the matter, different
medical specialists are collaborating with scientists of various disciplines, including physicists, mathematicians, computer scientists,
engineers, chemists and biologists.
96
Research Program
Research at DKFZ 2014
97
Imaging and Radiooncology
Radiology
Division
Head: Prof. Dr. Heinz-Peter Schlemmer
Radiology (E010)
German Cancer Research Center
Im Neuenheimer Feld 280
69120 Heidelberg
Phone: +49 6221 42 2563
[email protected]
The Division of Radiology is developing imaging methods for early detection of cancer and
characterizing their functional and biologic
features, e.g. blood supply, metabolism and
molecular mechanisms. In close cooperation with the other divisions of the research
program Ultrasonography (US), Computed
tomography (CT), Magnetic Resonance Imaging (MRI) and Positron Emission Tomography
Hybrid Imaging Devices (PET/CT and PET/MR)
are advanced and evaluated in patient studies.
For this purpose, up-to-date technologies are
available including ultra-high field MRI, dualenergy CT and PET/CT. Methodic developments
are conducted in cooperation with partners
from medical-technical and pharmaceutic
industries. Clinical studies are performed in
close cooperation with clinics and institutes
of the Heidelberg University hospital and the
National Center for Tumor Diseases (NCT) Heidelberg. The Devision is furthermore a partner
of the German Consortium for Translational
Oncology and the German Center for Lung
Research. Scientific fields of application include e.g. early detection and characterization
of prostate cancer, lung cancer and multiple
myeloma. A novel biopsy system combining
preinterventional MRI with peri-interventional
ultrasound for perineal prostate biopsies is
applied in co-operation with the Department
of Urology at Heidelberg University Hospital,
enabling precise diagnosis of prostate cancer.
In addition, tools for quantifying individual
therapy response are developed and applied
in patients with e.g. rectal carcinoma or malignant melanoma. Further activities include
the computer-aided image handling for implementation of the complex image information
in patient care, e.g. for improving radiotherapy.
A clinical phase 1 study with MR-guided intra-
urethral thermotherapy using high-intensity
focused ultrasound (HIFU) is currently going
on. A simultaneous PET/MR system has been
installed last year and successfully. It is used to
improve tumour characterisation, individualised therapy planning and therapy monitoring,
while concurrently reducing radiation burden
for the patient.
Future Outlook:
Our Goal is the progress of individualized
diagnostics and therapy and image-guided
therapy. Ultra-high field MRI is currently applied for advanced imaging of brain tumors.
Novel contrast media (CEST agents) will be
developed. Diffusion-weighted MRI for staging
and therapy control is applied in patients with
multiple myeloma. A cohort study supported
by the Jose-Carreras-foundation for evaluating prognostic significance of perfusion data
from dynamic MRI is currently in progress. In
patients with bronchogenic carcinoma, novel
approaches are developed for metabolic MRI,
4D-CT imaging and PET with new radiotracers. The CT-based “lung cancer screening and
intervention trial” (LUSI study) for early detection of bronchogenic carcinoma has been running over 5 years. Novel tools are developed to
quantify therapy response, e.g. dual-energy CT
for assessing changes in tissue composition.
ESSENTIAL PUBLICATIONS:
(1.) Re T.J. et al. (2011). Enhancing pancreatic adenocarcinoma delineation in diffusion derived intravoxel incoherent motion f-maps through automatic vessel and duct segmentation. Magn. Reson. Med., 66,
1327–1332.
(2.) Bauman G. et al. (2011). Pulmonary Functional Imaging: Qualitative Comparison of Fourier Decomposition MR Imaging with SPECT/CT in Porcine Lung.
Radiology, 260, 551–519.
(3.) Hillengass J. et al. (2011). Diffusion-weighted imaging for non-invasive and quantitative monitoring
of bone marrow infiltration in patients with monoclonal plasma cell disease: a comparative study with
Patient with a cerebral glioblastoma of
the left hemisphere. Axial high-resolution
T2-weighted MR at 7.0 Tesla demonstrating
tumor localization and heterogeneity.
98
Research Program
histology. Br. J. Haematol, 153, 721–728.
(4.) Hadaschik B.A. et al. (2012). A novel Stereotactic
Prostate Biopsy System Integrating Preinterventional
MRI and Live US fusion. J. Urology, 26, 807–813.
Imaging and Radiooncology
Medical Physics in Radiology
Division
Head: Prof. Dr. Mark E. Ladd
The Division of Medical Physics in Radiology
plays a pivotal role in all imaging-based diagnostic and therapeutic procedures, developing new and optimizing existing methods.
To improve and individualize cancer patient
treatment, the acquisition of quantitative
biomedical information about the metabolic,
physiologic, and functional parameters of tumors and metastases is essential. We are, for
example, expanding the diagnostic value of
magnetic resonance imaging (MRI) by using a
very powerful magnetic field (7 Tesla) to enable
the depiction of the distribution of sodium
(Na-23), oxygen (O-17), and even potassium
(K-39) in vivo. Through the extension of MRI
diffusion measurement techniques, we are
able to gain additional information about cellular membranes and incoherent capillary flow
in tumor tissue. Computed tomography (CT)
techniques that allow dramatic reductions in
radiation dose to enable CT fluoroscopy or that
reduce motion-induced artifacts are also the
focus of our work. Furthermore, we are developing noninvasive diagnostic methods for the
in vivo detection and functional characterization of metastases on the micro-morphological level. New targeted contrast agent designs
are being pursued that allow the attachment
of different imaging tags in a modular manner.
These concepts permit the use of multiple biophysical techniques (MRI, CT, Positron Emission
Tomography (PET), optical imaging) to monitor
molecular processes in a relevant pharmacological context.
Future Outlook:
The Division will continue its role as a center
of excellence in oncologic imaging methodology and expand and strengthen its support
of the clinical divisions. Novel acquisition and
reconstruction strategies are in development
for multiple tomographic modalities that are
targeted toward improving diagnostics and
therapy monitoring, and molecular imaging
methodologies are being pursued with a focus
on metastatic processes, including the further
Research at DKFZ 2014
development of multimodal small-animal tomographic systems. Major objectives for the
future involve research projects with the 7
Tesla system and the newly established hybrid
MRI-PET system. For example, we have a major
effort underway to overcome the technical
challenges of imaging the human torso at 7
Tesla. Success would allow us to translate techniques from the brain and take advantage of
the enhanced sensitivity of the high magnetic
field in organs like the liver, kidneys, and prostate. As part of a concerted initiative across
DKFZ divisions, we will be applying a multitude
of imaging techniques to improve the characterization of prostate cancer and thus avoid
unnecessary therapy.
ESSENTIAL PUBLICATIONS:
(1.) Kuder T.A. et al. (2013). Diffusion pore imaging by
hyperpolarized xenon-129 nuclear magnetic resonance. Physical Review Letters, 111, 028101.
(2.) Umathum R. et al. (2013). In vivo 39K MR imaging
Medical Physics in Radiology (E020)
of human muscle and brain. Radiology, 269, 569–576.
German Cancer Research Center
(3.) Flach B. et al. (2013). Low dose tomographic fluor-
Im Neuenheimer Feld 280
oscopy: 4D intervention guidance with running prior.
69120 Heidelberg
Medical Physics, 40, 101909.
(4.) Mühlhausen U. et al. (2011). A novel PET tracer for
the imaging of αvβ3 and αvβ5 integrins in experi-
Phone: +49 6221 42 2550
[email protected]
mental breast cancer bone metastases. Contrast Media & Molecular Imaging, 6, 413–420.
Conventional gadolinium contrast-enhanced
MRI (left) together with a pH-weighted amide
CEST image (right) of a brain tumor patient
(glioblastoma) obtained with the 7 Tesla MRI
system. Chemical Exchange Saturation Transfer
(CEST) imaging allows the detection of amide
protons in protein backbones by indirect
modulation of the water signal. The endogenous
amide CEST contrast delineates the tumor region
very similarly to the conventional image without
the need of an intravenously applied contrast
agent (Zaiss M. & Bachert P. (2013). Chemical
exchange saturation transfer (CEST) and MR
Z-spectroscopy in vivo: a review of theoretical
approaches and methods. Physics in Medicine
and Biology, 58, R221–R269).
99
Imaging and Radiooncology
Radiopharmaceutical Chemistry
Division
Head: Prof. Dr. Klaus Kopka
Radiopharmaceutical Chemistry (E030)
German Cancer Research Center
Im Neuenheimer Feld 280
69120 Heidelberg
Phone: +49 6221 42 2432
[email protected]
The Division Radiopharmaceutical Chemistry
designs targeted radiotracers for the molecular imaging and diagnosis of cancer by means
of positron emission tomography (PET) and
by the en-vogue hybrid technologies PET/CT
and PET/MRT, which are used for the highly
sensitive non-invasive imaging of biological
processes at the molecular level. The focus is
the visualisation of rather early disease states
or early inspection of treatment response after
chemotherapy, radiation therapy or targeted
internal radiation therapy (radioendotherapy)
in vivo. One main task is thus the development
of novel PET radiopharmaceuticals targeting receptors, transport systems and enzymes
relevant in early tumorigenesis and tumor
progression, to establish a tool for improving
the clinical management of patients suffering
from tumors, thereby advancing the identification or even the prevention of tumor dissemination.
Radiopharmaceutical Chemistry reverts to interdisciplinary fields, such as nuclear chemistry
using cyclotrons (see figure) and radionuclide
generators. Sub-fields such as labelling chemistry, medicinal chemistry, organic and solidphase chemistry are further required. To fulfil
the translation of new PET tracers into the
clinical scenario, special laboratory environments are needed to set up Good Manufacturing Practice (GMP)-compliant automated
radiosyntheses in highly sophisticated clean
rooms which comply with radiation protection
and also with the pharmaceuticals act.
as 18F, 68Ga and others, targeting enzymes such
as matrix metalloproteinases (MMPs) and the
prostate-specific membrane antigen (PSMA),
as well as membrane-associated receptors and
biological targets playing key roles in neoangiogenesis. The tailor-made diagnostic tracers
should be designed in such a way that they
can also be used as therapeutic pharmaceuticals which bear corresponding particle emitters such as 90Y, 177Lu and others (i.e. “in vivo
theranostic approach”, already established for
[68Ga]Ga- and [177Lu]Lu-DOTATOC). We speculate that the non-invasive in vivo visualisation
of these biological targets by those targetaffine radiotracers will elucidate still unsolved
clinical oncological questions - benefiting the
patient in any case.
With respect to the aforementioned aspects,
the Division Radiopharmaceutical Chemistry
fits elegantly into the context of the research
program Imaging and Radiooncology (FSE).
The motivation is to directly link basic research
expertise to the GMP-compliant production
of corresponding PET tracers for clinical research, as is the case with [18F]FDG, [18F]FLT, [18F]
FET, Na[18F]F, [68Ga]Ga-DOTATOC and [68Ga]GaPSMA, to support cancer research at dkfz. In
this regard close cooperation with the clinical
cooperation unit Nuclear Medicine is indispensable.
ESSENTIAL PUBLICATIONS:
(1.) Eder M. et al. (2013). Pharmacokinetic Properties
of Peptidic Radiopharmaceuticals: Reduced Uptake
Future Outlook:
Notably, the Division Radiopharmaceutical
Chemistry will focus on the development of
peptidyl and non-peptidyl tracers, i.e. radiolabelled with PET-compatible radionuclides, such
of (EH)3-Conjugates in Important Organs. J Nucl Med,
54, 1327–1330.
(2.) Hugenberg V. et al. (2013).Inverse 1,2,3-triazole1-yl-ethyl substituted hydroxamates as highly potent
matrix metalloproteinase inhibitors: (Radio)synthesis, in vitro and first in vivo evaluation. J Med Chem,
56, 6858–6870.
Negative ion 32 MeV
cyclotron MC32NI at dkfz
for the production of
radionuclides (length x
width x height = 4.0 m
x 3.5 m x 2.2 m; weight =
60 t).
(3.) Waldmann C. et al. (2013). A Closer Look at the
Bromine Lithium Exchange with tert Butyllithium in
an Aryl Sulfonamide Synthesis. Org Lett, 15, 2954-2957.
(4.) Schrigten D. et al. (2012). A New Generation of Radiofluorinated Pyrimidine-2,4,6-triones as MMP-targeted Radiotracers for Positron Emission Tomography. J Med Chem, 55, 223–232.
100
Research Program
Imaging and Radiooncology
Medical Physics in Radiation Oncology
Division
Head: Prof. Dr. Oliver Jäkel
Because failure of local tumor control is still
a problem in many cancer patients, there is
an urgent need to optimize existing and to
develop new and more effective radiotherapy
techniques for localized tumors. Research at
our devision is focusing on new conformal radiotherapy techniques with photons, electrons,
protons and heavy ions. In the framework of
ongoing projects in photon and ion therapy,
the division future work will concentrate on
the consideration of dynamic changes of target volumes and organs at risk under therapy,
due to therapeutic response, organ movement
or patient repositioning. Image-guided and
time-adapted therapy is being developed to
combine conformal dose delivery with online
imaging of 3D anatomy and online monitoring
of 3D dose distributions. The devision is furthermore integrating molecular imaging into
treatment planning and dose delivery with the
goals of boosting radio-resistant tumor subvolumes and avoiding radiosensitive normal
tissue structures. Establishing mathematical
and biological models of tumor and normal
tissue response is a further tool to optimize
treatment schemes and techniques. One of the
strengths of the division is the direct transfer
of prototypes of software and hardware development into clinical applications in close
collaboration with the Clinical Cooperation
Unit Radiation Oncology. Thus the devision
is also active in testing and evaluating new
techniques, as well as in establishing adequate
quality assurance programs.
eration of treatment machines. To support the
general aim of a biologically guided radiotherapy at DKFZ, we will pursue the development
of a unified treatment planning and optimization platform that specifically accounts for the
information provided by biological input data.
In heavy ion therapy, new dosimetric methods
will be developed. A project for Monte Carlo
simulation of the effects of secondary electrons in the dosimetry of heavy ions and the
investigation of perturbation factors for ionization chamber dosimetry has been started. The
possibility to use radiographic imaging or even
MRI with ion beams will be investigated for ion
beam treatment.
A further essential development is a method
to visualize ion tracks in cell layers on nuclear
track detectors, as a tool to investigate radiobiological properties of clinical ion beams.
ESSENTIAL PUBLICATIONS:
(1.) Moser T. et al. (2013). Clinical Evaluation of a Laser
Medical Physics in Radiation Oncology (E040)
Surface Scanning System in 120 Patients for Improv-
German Cancer Research Center
ing Daily Setup Accuracy in Fractionated Radiotherapy. International Journal of Radiation Oncology Biolo-
Im Neuenheimer Feld 280
gy Physics, 85, 846–853.
69120 Heidelberg
(2.) Espinoza I. et al. (2013). A model to simulate the
Phone: +49 6221 42 2540
oxygen distribution in hypoxic tumors for different vascular architectures. Med Phys. 40, 081703. doi:
[email protected]
10.1118/1.4812431.
(3.) Niklas M. et al. (2013). Ion track reconstruction using alumina-based fluorescent nuclear track detectors. Physics in Medicine and Biology, 58, N251–N266.
(4.) Bangert,M. et al.: Analytical probabilistic modeling for radiation therapy treatment planning. Physics
Future Outlook:
The future research and development projects
comprise the fields of image-guided radiotherapy (IGRT), biological adaptive radiotherapy,
ion therapy and the physical parts of different
radiation biology projects. Research related to
IGRT with photons will be followed by a phase
where the results are transferred to the clinical
application at DKFZ. We want to accompany
the development of real-time 3D-imaging of
the patient in treatment position. Promising
new approaches involve combinations of MRimaging or 3D x-ray imaging with a new gen-
Research at DKFZ 2014
in Medicine and Biology, 58 (16), 5401-5419, 2013.
A method of co-localization of ion beam irradiation
and cellular response on a fluorescence nuclear
track detector (FNTD) has been developed in the
department (Niklas et al. PMB 2013). Microscopic
images from the FNTD enable the investigation
of particle tracks from ion beams (shown in red)
and their biological effects in the cell nuclei (DSB=
double strand breaks of the DNA, green).
101
Imaging and Radiooncology
Radiation Oncology
Clinical Cooperation Unit
Head: Prof. Dr. Dr. Jürgen Debus
Radiation Oncology (E050)
German Cancer Research Center
Im Neuenheimer Feld 280
69120 Heidelberg
Phone: +49 6221 42 2515
[email protected]
Intensity-modulated radiotherapy of a
pelvic tumor. Individualized beams from 9
directions enable personalized treatment
with sparing of sensitive structures such as
small bowel, bladder and genitals (Raystation
planning software, Raysearch Laboratories,
Stockholm, Sweden).
The Clinical Cooperation Unit Radiation Oncology treats cancer patients with new innovative technologies in challenging situations.
It explores new approaches and pushes the
boundaries of modern radiation oncology.
This involves the combination of different
radiotherapy techniques such as intensity
modulated radiotherapy (IMRT), intraoperative
radiotherapy and brachytherapy. New software
solutions for optimzed combination of photon
and particle treatment in cooperation with the
Heidelberg Ion Therapy facility (HIT) are being
established. One research focus is the treatment of moving tumors in the lung and upper
abdomen. Breathing motion adjusted therapy
is applied in so called gated therapy; Radiation is only delivered in the optimal breathing phase and thus safety margins can be
minimized and dose exposure to surrounding
tissues lowered. Different markers invasively
placed around the tumor are evaluated to improve imaging of tumor motion and allow for
gated or tracked therapy. This includes gold
markers for x-ray based fluoroscopy imaging
and electromagnetic markers for online tumor
motion tracking. Another option in high precision radiotherapy is rotational intensity-modulated therapy (IMRT). Its possibilities alone or
in combination with static gantry IMRT (hybrid
arc) are being explored. Another research focus
is the evaluation of functional imaging in the
planning of radiotherapy. This includes metabolic and hypoxic tracers and their potential to
individualize radiation treatment of non-small
cell lung cancer.
initial step two separate machines – a linear
accelerator and an independant 1.5 T MR – are
planned to be linked with a patient shuttle to
allow MRI based position control and correction. The aim is to minimize additional dosage
(especially in younger patients and children)
and to improve soft tissue contrast for tumor
position detection. The next step in this evolution of modern IGRT is going to be a linear
accelerator-MRI combination in one machine
for accelerated workflow and online tumor
imaging. A clinical focus will be on the possibilities of radiosurgery of spinal tumors. While
this is traditionally the domain of conventional
radiotherapy, new options for radiosurgical
approaches will be tested in a prospective, randomized manner. New radiotherapy options
using a robotic arm approach for indiviualized
and personalized targeted radiation oncology
are also on the agenda. The expansion of radiosurgical and fractionated therapy options
is the goal. In medical oncology a remarkable
flood of new substances targeting specific
tumor pathways has been seen. The combination of these drugs with radiation therapy and
the implications for normal tissue toxicity is a
major challenge in the future and shall be addressed in an experimental and clinical setting
to ensure the safety of these multimodal cancer therapy approaches.
ESSENTIAL PUBLICATIONS:
(1.) Roeder F et al. (2012). Aggressive local treatment
containing intraoperative radiation therapy (IORT) for
patients with isolated local recurrences of pancreatic
cancer:a retrospective analysis. BMC Cancer, 12, 295.
Future Outlook:
In cooperation with the department of diagnostic radiology, the use of an MRI/PET for
target definition and treatment planning in radiation oncology will be explored. This includes
new radiotracers and special MRI sequences
for whole body imaging and the detection of
lymph node metastases. In addition, the integration of MR imaging into image guided
radiotherapy (IGRT) shall be established. In an
102
Research Program
(2.) Roeder F. et al. (2011). Intensity modulated or fractionated stereotactic reirradiation in patients with
recurrent nasopharyngeal cancer. Radiat Oncol, 6, 22.
(3.) Zwicker F. et al. (2011). Reirradiation with intensitymodulated radiotherapy in recurrent head and neck
cancer. Head Neck, 33, 1695–1702.
(4.) Sterzing F. et al. (2009). Intensity modulated radiotherapy (IMRT) in the treatment of children and adolescents--a single institution’s experience and a review of the iterature. Radiat Oncol, 4, 37.
Imaging and Radiooncology
Molecular Radiooncology
Clinical Cooperation Unit
Head: Prof Dr. Dr. Peter Huber
The goal of current molecular research in
Radiation Oncology is to work towards a personalized medicine program, applying highthroughput methodologies in preclinical and
translational research trials. Genetic key players in radioresistance and the determinants
of recurrences after radiotherapy are being investigated to broaden the therapeutic window
and improve clinical outcome in radiotherapy
cancer patients. To this end, we are conducting investigations in preclinical and clinical
research in the following areas:
• Can radiation favorably be combined with
specific signaling inhibitors to enhance
therapeutic anti-tumor efficacy +/- CTX of
VEGF, PDGF, EGF, Integrins, TGF-beta etc.?
• Can combinations of signaling inhibitors
(PDGF, TGF-beta, CTGF) attenuate radiotherapy-associated side effects such as
lung fibrosis?
• Prospective trials investigating the immune stimulatory effects of low dose
irradiation in tumor patients (pancreatic
cancer, liver metastases from CRC, lung
cancer)
• Translational clinical studies investigating
if radiotherapy (IMRT) can be successfully
combined with EGFR or other signaling
inhibitors in NSCLC and pancreatic cancer
• The molecular basis of the efficacy of carbon ion/particle radiotherapy
• The network governing the angiogenic
switch or other balanced systems in irradiated cancer
• The feasibility of MRI-guided focused ultrasound induced tumor therapy
• New clinical concepts of intensity-modulated radiotherapy treatment using biophysical/molecular/functional imaging
strategies.
gies, such as genomics, functional genomics,
epigenetics, proteomics, siRNA screening, bioinformatics, systems biology approaches and
molecular and macroscopic radiological imaging. These categories will be linked to classical cancer research expertise in areas such as
apoptosis, immunology, stem cell biology, angiogenesis, fibrogenesis, and carcinogenesis or
signal transduction. A major goal of Molecular
Radiation Oncology is the clinical and biomedical analysis of radiation tumor/normal tissue
biology. Key genetic players of radiation effects
can be identified by global expression profiling
(genomics/proteomics)
and sequencing studies in tumor/blood samples in preclinical cell and animal studies, but
also in cancer patients undergoing clinical
trials. The promising “targets” can be further
functionally evaluated for their ability to
modulate radiotherapy response by knock outs
or pharmacological intervention. The resulting
data can then be used to rationally design “targeted drug cocktails” for preclinical cell and
animal research and finally, for the translation
to cancer patients. To optimize and personalize
cancer therapies in the future, we will perform
bench-to-bedside research including initiation
and conduction of clinical studies.
ESSENTIAL PUBLICATIONS:
(1.) Klug F et al. (2013). Low-Dose Irradiation Programs
Macrophage Differentiation to an iNOS+/M1 Phenotype that Orchestrates Effective T Cell Immunotherapy. Cancer Cell, 24, 589–602.
(2.) Flechsig P. et al. (2012). LY2109761 attenuates radi-
Molecular Radiooncology (E055)
German Cancer Research Center
Im Neuenheimer Feld 280
69120 Heidelberg
Phone: +49 06221 42 2515
[email protected]
Magnetic resonance imaging of a mouse brain
with a glioblastoma tumor. Blockade of TGF-beta
signaling by the TGFβR-I kinase Inhibitor LY2109761
(LY) enhances radiation response (RT) and prolongs
survival in glioblastoma in an orthotopic mouse
model.
ation-induced pulmonary murine fibrosis via reversal of TGF-beta and BMP associated proinflammatory and proangiogenic signals. Clin Cancer Res, 18,
3616–3627.
(3.) Zhang M. (2011). Blockade of TGF-beta signaling
by the TGFβR-I kinase Inhibitor LY2109761 enhances
Future Outlook:
An important goal for Radiation Oncology in
the future is the systematic analysis of molecular radiation effects. Aims are the integration
of radiation research topics with high throughput biology and radiology platform technolo-
Research at DKFZ 2014
radiation response and prolongs survival in glioblastoma. Cancer Research, 71, 7155–7167.
(4.) Timke C. (2011). Randomized controlled phase I/II
study to investigate immune stimulatory effects by
low dose radiotherapy in primarily operable pancreatic cancer. BMC Cancer, 11, 134.
103
Imaging and Radiooncology
Nuclear Medicine
Clinical Cooperation Unit
Head: Prof. Dr. Uwe Haberkorn
The Clinical Cooperation Unit (CCU) Nuclear
Medicine is involved in multiple projects on
topics such as the planning and follow up of
chemo- or radiation therapy, pharmacokinetic
modelling of dynamic PET data, identification
of new peptides with high affinity for tumor
disease; the establishment of new endoradiotherapy approaches based on peptides and
antibodies; the development of alternate panning strategies with phage and ribosome display using recombinant proteins, membrane
fractions and cells; the design of combination
therapy with endoradiotherapy and chemo-,
immuno- or radiation therapy; and the establishment of new treatments for non-iodineconcentrating thyroid carcinoma.
Future Outlook:
One major topic for the CCU Nuclear Medicine’s future research will be the identification of possible targets for new radiopharmaceuticals. For this purpose, the gene array
data obtained from correlative PET and tumor
specimen evaluations are screened for receptors and cell surface proteins. Following the
identification of possible targets, the partners
at the MPI Saarbrücken are using their FLEXx
software, a small molecule docking software,
to identify substances with a high likelihood of
binding to the identified structures.
Nuclear Medicine (E060)
German Cancer Research Center
Im Neuenheimer Feld 280
69120 Heidelberg
Phone: +49 6221 42 2477
[email protected]
The identification of new ligands will be one
of the main areas of research in the laboratory. The group intends to apply biotechnology
methods such as display (phage and ribosome
display) of libraries consisting of scaffold proteins. This project addresses the identification
of specific binders to targets overexpressed
in a variety of tumors by using peptide libraries. We will concentrate on target structures
identified either by literature research or by
gene profiling data available at the campus.
In the last 18 months we started intra-arterial
therapy with DOTATOC in patients with metastasized neuroendocrine tumors using 90Y,
177Lu and 213Bi. This program will be extended
to other peptides/receptors. Furthermore,
novel treatment strategies, using radiolabelled
benzamides in melanoma patients and PSMA
ligands in patients with prostate carcinoma,
have been successfully transferred into clinical
application.
ESSENTIAL PUBLICATIONS:
(1.) Kratochwil C. et al. (2010). Intraindividual comparison of selective arterial versus venous 68Ga-DOTATOC-PET/CT in patients with gastroenteropancreatic
neuroendocrine tumors. Clin Cancer Res, 16, 2899–
2905.
(2.) Strauss L.G. et al. (2011). Shortened acquisition
protocols for the quantitative assessment of the
2-tissue compartment mod-el using dynamic PET/CT
18F-FDG studies. J Nucl Med, 52, 379–385.
(3.) Zoller F. et al. (2013). A Disulfide-Constrained Miniprotein with Striking Tumor-Binding Specificity Developed by Ribosome Display. Angewandte Chemie
Int Edition, 52, 11760–11764.
(4.) Altmann A. et al. (2010). Therapy of thyroid carcinoma with the histone deacetylase inhibitor MS-275.
Eur J Nucl Med Mol Imaging, 37, 2286-2297.
prior
104
after
Research Program
PET/CT with a Ga-68 labelled
PSMA ligand prior and after
endoradiotherapy with a
I-131 labelled PSMA ligand in
a patient with biochemical
recurrence and multiple
lymph node metastases. After
one cycle, a decrease in tracer
accumulation and a reduction
of the number of metastases
was seen.
Imaging and Radiooncology
Medical and Biological Informatics
Division
Head: Prof. Dr. Hans-Peter Meinzer
Research in our division aims at improving
diagnostic methods and treatment planning
based on imaging technologies, such as computer tomography, magnetic resonance tomography and ultrasound.
The division is currently active in different
research areas of medical imaging, including image analysis for tissue differentiation,
simulation and diffusion imaging. A recently
established junior group is working on new
methods in the field of computer assisted interventions.
Central to our work is the idea of translational
research, i.e. translating our findings, methods and software to the patient in the clinic.
Therefore, we are closely collaborating with
a large number of national and international
hospitals, as well as various engineering institutes. Furthermore, we established a quality
management process for our central software
platform MITK (Medical Imaging Interaction
Toolkit).
Future Outlook:
Since 2002 MITK, which is the central element
of our research, has been the basis for all developments of the devision of Medical and
Biological Informatics and is undergoing continuous development. In a joint effort to facilitate the international collaboration between
different research groups, the Common Toolkit
(CTK) project was initiated in 2009 by Prof.
Dr. Ron Kikinis (Harvard Medical School) and
Prof. Dr. Hans-Peter Meinzer, head of the MBI
division. In this initiative, different research
groups and companies from around the world
are together developing a new common basis
for software development in medical imaging.
Another central orientation is microstructural analysis of the brain based on diffusionweighted magnetic resonance imaging (dMRI).
As an example dMRI can help in detecting
Alzheimer disease at an early stage. In surgical navigation, we are focusing on markerless
localization of patient and instruments by
means of Time-of-Flight (ToF) cameras which
provide depth information in addition to a
Research at DKFZ 2014
standard two-dimensional image. Concerning
image analysis, we are involved in an obesity
study with over 1200 patients. Further work
focuses on automated differentiation of fat
tissue in whole body MR images, which allows
for examining the influence of distinct fat tissue types. A very recent development in our
division is the use of portable devices, such as
tablet computers, as both a radiological viewer
and to assist surgical navigation. Additionally,
the division is part of the recently established
collaborative research center “Cognition Guided Surgery”.
ESSENTIAL PUBLICATIONS:
(1.) Fritzsche K.H. et al. (2012). MITK Diffusion Imaging. Methods of Information in Medicine, Methods Inf
Med., 51, 441–418.
(2.) van Bruggen T. et al. (2012). Do Alzheimer specific microstructural changes in mild cognitive impairment predict conversion? Psychiatry Res, 203(2-3),
184–193.
(3.) Wald D. et al. (2012). Automatic Quantification
Medical and Biological Informatics (E130)
of Subcutaneous and Visceral Adipose Tissue from
German Cancer Research Center
Whole-Body Magnetic Resonance Images suitable for
Large Cohort Studies. Journal of Magnetic Resonance
Im Neuenheimer Feld 280
Imaging, 36, 1421–1434.
69120 Heidelberg
(4.) Maier-Hein L. et al. (2012). Convergent Iterative
Phone: +49 6221 42 2354
Closest-Point Algorithm to Accomodate Anisotrop-
[email protected]
ic and Inhomogenous Localization Error. IEEE Transactions on Pattern Analysis and Machine Intelligence,
34, 1520–1532.
Three-dimensional reconstruction
of an individual liver. The blood
supply through the portal vein
(light blue), the hepatic veins (dark
blue), arteries (red), gall bladder
(green) and three tumors (red),
including safety margins (yellow),
are shown.
105
Imaging and Radiooncology
Optical Nanoscopy
Division
Head: Prof. Dr. Stefan Hell
The resolution of light microscopes has been
generally limited by the wavelength of light to
about 250 nanometers. We have developed the
first fluorescence microscopes capable of providing images with a resolution of fractions of
light’s wavelength from the interior of a cell. A
combination of two of our approaches, namely
4Pi and STED microscopy, makes it possible to
achieve resolutions under 40 nanometers in
all directions. This enables us to observe biological structures that are 2000 times thinner
than a human hair. We are now trying to find
out how we can achieve and exploit resolutions in the range of a few nanometers to
fundamentally advance biological and clinical
research.
Future Outlook: Our goal is to develop techniques such as STED (Stimulated Emission
Depletion Microscopy) to unveil sub-cellular
structures at a resolution level of a few 10 nm
in a living cell. After all, every disease manifests
itself first in the cells. We are now exploring
how the breakthrough in light microscopy resolution can be translated into fundamental advancements in biological and clinical research.
STED light microscopy makes it possible to
study the causes of diseases more closely and
thus to speed up development of medications.
Optical Nanoscopy (E190)
German Cancer Research Center
Im Neuenheimer Feld 280
69120 Heidelberg
Phone: +49 6221 54 51210
and +49 551 201 2500
[email protected]
and Max Planck Institute for Biophysical
Chemistry in Göttingen, Department of
NanoBiophotonics
106
Research Program
ESSENTIAL PUBLICATIONS:
(1.) Chojnacki J. et al. (2012). Maturation-Dependent
HIV-1 Surface Protein Redistribution Revealed by Fluorescence Nanoscopy. Science, 338, 524–528.
(2.) Vicidomini G. et al. (2012). STED with wavelengths
closer to the emission maximum., Opt Express, 20,
5225–5236.
(3.) Bingen P. et al. (2011). Parallelized STED fluorescence nanoscopy. Opt Express, 19, 23716–23726.
(4.) Berning S. et al. (2012). Nanoscopy in a living
mouse brain. Science, 335, 551.
Vimentin network of mammalian
cell revealed by STED fluorescence
microscopy with subdiffraction
spatial resolution.
Research at DKFZ 2014
107
Imaging and Radiooncology
Translational Radiation Oncology
Max-Eder-Junior Research Group
Head: Dr. Dr. Amir Abdollahi
Translational Radiation Oncology (E210)
German Cancer Research Center
Im Neuenheimer Feld 450
69120 Heidelberg
Phone: +49 6221 56 39604
[email protected]
Abdollahi’s group was one of the first to employ genome-wide transcriptional analysis and
protein phosphorylation analysis to systematically investigate the perturbation of the cellular homeostasis induced by ionizing radiation
and anti-/pro-angiogenesis. These discoveries
have built a foundation to better understand
inter-cellular communication and intra-cellular signalling principles induced by radiation
and angiogenesis modulators, and unravelled
key mechanisms governing tumor therapy resistance – a major obstacle of cancer therapy.
Their data indicate that tumor-stroma and
tumor-vessel communication i.e., microvasculature endothelial cells, constitute a critical
target of conventional cancer therapies, such
as radiation and chemotherapy. Subsequently,
molecular, cellular and physiological rationales
for the beneficial use of trimodal cancer therapy (consisting of anti-angiogenesis, radiotherapy and chemotherapy) were provided. The
translational impact of this research on the
development of novel clinical protocols is evident from the growing number of trimodal trials in solid tumors initiated in Heidelberg and
worldwide. Intriguingly, they could also show
that inhibition of PDGF signaling ameliorates
the development of radiation-induced lung
fibrosis, a critical side effect and dose limiting
normal tissue response of radiotherapy. In addition, this group has recently discovered the
potential of peripheral blood transcriptome
and miRs as a sentinel organ to properly detect
tumor stage and predict clinical outcome.
Future Outlook:
A major goal of this group is to generate an
integrative molecular biology platform for
identification of cell-cell and intracellular signaling networks induced by photon, proton and
carbon irradiation incorporating transcriptomics, miRNA, epigenomics, proteomics and
functional genomics approaches. These data
will be instrumental in identification of novel
molecular targets for modulating the radiation
response, i.e., enhancing the anti-tumor effects
while sparing surrounding normal tissue from
radiation induced damage. They further aim
to better understand the mechanism of local
invasion and distant metastasis of tumors.
The field of radiotherapy still lacks powerful
biomarker and molecular classifiers of therapy
response. Accordingly, they seek to design peripheral blood transcriptome and miRNA based
patient classifier that would assist clinicians in
selecting those patients likely to benefit most
from the local multimodal therapies. Finally,
the group aims to optimize local tumor control
via rational design of multimodal therapies
consisting of radiotherapy and tumor stroma
targeting agents. A critical step towards this
goal is the systematic investigation of compensatory mechanisms that render tumors
resistant to radiotherapy and targeted i.e., antiangiogenic, cancer therapies.
ESSENTIAL PUBLICATIONS:
(1.) Abdollahi A. et al. (2010). Evading tumor evasion:
Current concepts and perspectives of anti-angiogenic cancer therapy. Drug Resist Updat., 13, 16–28.
(2.) Almog N. et al. (2009). Transcriptional Switch of
Dormant Tumors to Fast-Growing Angiogenic Phenotype. Cancer Research., 69, 836–844.
(3.) Abdollahi A. et al. (2007). Transcriptional network
governing the angiogenic switch in human pancreat-
From left: establishment of
first preclinical models of lung
irradiation with carbon ions,
examples for verification of
carbon ion dose distribution
by PET/CT, evaluation of
radiation-induced lung
toxicity and microvascular
damage. Clinical translation
(right): irradiation of the first
lung cancer patient with
carbon ions at HIT in fall 2011.
108
Research Program
ic cancer. Proc Natl Acad Sci U S A., 104, 12890–1285.
(4.) Abdollahi A. et al. (2005). Inhibition of plateletderived growth factor signaling attenuates pulmonary fibrosis. J Exp Med., 201, 925–935.
Imaging and Radiooncology
Computer-assisted Interventions
Junior Research Group
Head: Dr. Lena Maier-Hein
Medical interventions involving minimallyinvasive access to the internal anatomy of the
patient are continuously gaining importance
in the diagnosis and treatment of cancer and
other diseases. The safety, efficiency and success of such interventions crucially depend on
the precise navigation of medical instruments
through the patient’s body, while taking critical structures into account. However, mental
fusion of the partially visible anatomy with
high-resolution pre-operative tomographic images and/or surgical planning data in the presence of organ motion is extremely challenging.
Our multidisciplinary research group, which is
associated with the Division of Medical and Biological Informatics, combines expertise from
computing, physics and medicine in order to
develop new concepts for computer-assisted
medical interventions. Our focus is on technological innovation with a strong emphasis on
clinical translation and direct patient benefits.
Current research topics include robust and fast
3D localization of the patient anatomy using
range imaging techniques, such as Time-ofFlight, real-time fusion of multi-modal patient
data based on surface registration and new
tracking techniques, as well as innovative human-computer interfaces. Further core areas
include the modeling and propagation of system errors as well as workflow optimized approaches to computer guidance that balance
the patient benefits with the complexity and
cost of the assistance system.
actions in a knowledge-based manner. Computer assistance shall cover the entire medical
workflow from treatment planning, to plan
execution, to follow-up, thereby supporting
the physician without adding complexity or
time compared to the conventional procedure.
To maximize patient safety, the uncertainties
associated with the different sources of information applied in the course of computerassisted treatment shall be properly modeled,
propagated and fused. Finally, a flexible technical infrastructure will allow straightforward
integration of new algorithms and devices and
fast adaption to the dynamic advances in surgical and interventional techniques. Eventually,
holistic analysis of all relevant data, objectivity
in data interpretation and context-aware assistance will lead to improved clinical outcome.
ESSENTIAL PUBLICATIONS:
(1.) Maier-Hein L. et al. (20.13). Optical Techniques for
3D Surface Reconstruction in Computer-assisted Lap-
Computer-assisted Interventions (E131)
aroscopic Surgery. Med Imag Anal, 17, 974–996.
German Cancer Research Center
(2.) Maier-Hein L. et al. (2012). Convergent iterative
Im Neuenheimer Feld 280
closest-point algorithm to accomodate anisotropic
and inhomogenous localization error. IEEE T Pattern
69120 Heidelberg
Anal, 34, 1520–1532.
Phone: +49 06221 42 2341
(3.) Seitel A. et al. (2011). Computer-assisted trajecto-
[email protected]
ry planning for percutaneous needle insertions. Med
Phys, 38, 3246–3259.
(4.) Maier-Hein L. (2008). In vivo accuracy assessment
of a needle-based navigation system for CT-guided radiofrequency ablation of the liver. Med Phys, 35,
5385–5396.
Future Outlook:
In the field of computer-assisted medical interventions, the immense capabilities of computers in terms of storing and processing huge
amounts of data have not yet been fully exploited. The vision of our group is to improve patient
care by an objective, context-aware and combined analysis of all relevant data in the course
of disease treatment. Dynamically acquired factual and practical knowledge (e.g. study results,
clinical outcomes in similar cases) as well as individual patient data (e.g. laboratory data, preoperative images, intra-operative sensor data)
shall be continuously accumulated and processed to support the physician’s decisions and
Research at DKFZ 2014
Computer-assisted
radiofrequency
ablation (RFA) of
the liver.
109
Coordinator
Prof. Dr. Lutz Gissmann
Infection and Cancer
Viruses play a crucial role in a number of cancers. This Research Program investigates the mechanisms by which viruses cause cancer
and the ways by which the body defends itself. In addition, researchers are isolating and characterizing unknown viruses from tumor
material. Special attention is directed to the diagnosis, prevention,
and treatment of such viral infections. Furthermore, scientists are
working on methods using viruses to selectively kill cancer cells
or as vehicles for introducing therapeutic genes into cells. Current
focuses of tumor-virological research are:
•
•
•
•
•
110
Papilloma viruses and their role in cancers of the genital organs, the mouth and throat, and the skin
Parvoviruses as direct inhibitors of tumor growth and as gene
vectors for cancer treatment
Retroviruses (HIV, spumaviruses) for developing specific therapies
Anelloviruses (TT viruses) and their effect on the host cell
genome
Herpesviruses (Epstein-Barr viruses) in the development of
malignant tumors and as gene vectors for cancer therapy.
Research Program
Research at DKFZ 2014
111
Infection and Cancer
Tumorvirology
Division
Head: Prof. Dr. Jean Rommelaere
Tumorvirology (F010)
German Cancer Research Center
Im Neuenheimer Feld 242
69120 Heidelberg
Phone: +49 6221 42 4960
[email protected]
The Division Tumor Virology should actually be
called “Anti-Tumor Virology” since its objective
is to develop oncolytic viruses (preferentially
killing tumor cells) and viral vectors (transferring therapeutic genes into diseased, including
cancer, cells). Our activities have led to the
launching of a clinical trial using the oncolytic
parvovirus H-1PV to treat malignant gliomas,
and the advanced validation of adeno-associated virus (AAV)-based vectors. Three main
research axes are presently developed.
1. Investigation of the interactions of oncolytic parvoviruses (PV) with host cells, in
particular
(i) cellular markers predictive of tumor responsiveness to PV treatment,
(ii) PV determinants of host range,
(iii) molecular pathways involved in PV
oncotoxic and immuno-modulating properties,
(iv) PV-mediated delivery of cyto- and
chemokines into tumors and their microenvironment.
2. Proofs of concept for future clinical trials
using oncolytic parvoviruses, including
(i) preclinical evaluation of the applicability of H-1PV therapy to malignancies in
children and adolescents,
(ii) development of novel anticancer strategies based on combining of H-1PV with
epigenetic modulators,
(iii) study of immuno-modulating effects
of H-1PV to optimize its use to treat pancreatic carcinomas.
3.
Our Virus Production & Development
Unit standardizes protocols for virus application to humans, and supports trialaccompanying research.
Future Outlook:
Basic research will be pursued to unravel the
cellular and parvoviral determinants of cell
permissiveness and killing, respectively. This
program is expected to contribute to identify
patients susceptible to oncolytic virus-based
treatments (“customized” therapy). Furthermore, our ambition is also to understand and
optimize the interplay between parvovirus
oncolytic effects and host anti-tumor immune
responses (through parvovirus arming with
chemokines or modulation of critical steps of
the viral life-cycle, in particular egress). On the
translational level, our work aims to broaden
the range of indications for a potential H-1PVbased oncolytic virotherapy. In order to prepare
future clinical trials, besides the glioma study
already under way, optimal treatment strategies combining parvoviruses with different
classes of antineoplastic and immunomodulating agents will be tested, using various in
vitro and in vivo models. On the basis of promising pre-clinical data, priority will be given
to clinical validation of treatment efficacy in
pancreatic carcinoma patients and in patients
with relapsed or refractory tumors in the field
of pediatric neuro-oncology.
ESSENTIAL PUBLICATIONS:
(1.) Li J. et al. (2013). Synergistic combination of valproic acid and oncolytic parvovirus H-1PV as a potential
therapy against cervical and pancreatic carcinomas.
EMBO Molecular Medicine, 5, 1537–1555.
Treatment of an
intracerebral rat glioma
with parvovirus H-1
(H-1PV). MRI of a rat brain
bearing a glioma, at the
time of infection with
H-1PV (left), and 8 days
later (right), showing
disappearance of the
tumor after infection.
(2.) Bär S. et al (2013). Vesicular transport of progeny parvovirus particles through ER and Golgi regulates maturation and cytolysis. PLOS Pathogens, 9,
e1003605. Doi:10.1371/journal.ppat.1003605.
(3.) Nüesch J.P.F. et al (2012). Molecular pathways: rodent parvoviruses: mechanisms of oncolysis and
prospects for clinical cancer treatment. Clinical Cancer Research, 18, 3516–3523.
(4.) Geletneky K. et al (2010). Regression of advanced
rat and human gliomas by local or systemic treatment with oncolytic parvovirus H-1 in rat models.
Neuro-Oncology, 12, 804–814.
112
Research Program
Infection and Cancer
Genome Modifications and Carcinogenesis
Division
Head: Prof. Dr. Lutz Gissmann
We have a long-standing interest in the immune response against Human Papillomaviruses (HPV) focusing on the question whether
antibodies directed against certain viral proteins can influence the natural cause of an infection and whether they can predict its clinical outcome. At present we investigate the
potential of an HPV vaccine to prevent recurrence of genital warts and are studying the
possibility to cure chronic infections by activation of HPV-specific T cells.
ESSENTIAL PUBLICATIONS:
By the aid of a high-throughput platform for
simultaneous detection of different antibodies
or nucleic acids that has been developed in our
laboratory, we are analyzing large sample collections from epidemiologic studies aiming at
the identification of papillomaviruses and other infectious agents (viruses and bacteria) as
causal factors for certain kinds of cancer where
such an involvement has as yet not been demonstrated. Using our technology we will investigate whether specific HPV mRNAs are
suitable biomarkers for early detection of HPVinduced cervical cancer.
(4.) Schädlich L. et al. (2009). Analysis of modified
(1.) Senger T. et al. (2010). Virus-like particles and capsomeres are potent vaccines against cutaneous alpha HPVs Vaccine. Vaccine, 28, 1583–1593.
(2.) Schmitt M. et al. (2010). Diagnosing Cervical Cancer and High-Grade Precursors by HPV16 Transcription Patterns. Cancer Res, 70, 249–256.
(3.) Dell K. et al. (2006). Intransasal immunization
with human papillomavirus type 16 capsomeres in
the presence of non-toxic cholera toxin-based adjuvants elicits increased vaginal immunoglobulin levels. Vaccine, 24, 2238–2247.
HPV 16 L1 capsomeres: The ability to assemble into
larger particles correlates with higher immunogenicity. J Virol, 83, 7690–7705.
Genome Modifications and Carcinogenesis
(F020)
German Cancer Research Center
Im Neuenheimer Feld 242
69120 Heidelberg
The program on Foamy Viruses from different
animal species deals with their host restriction and the evaluation of a possible inter-species transmission (zoonosis) thereby potentially acquiring transforming properties also in
humans.
Phone: +49 6221 42 46 03
[email protected]
We also study the role two classes of molecules (cyclooxygenases and lipoxygenases)
that are central in chronic inflammation which
is a well-defined risk factor for cancer development.
Instrumentation for multiplex
serology and multiplex genotyping
Research at DKFZ 2014
113
Infection and Cancer
Viral Transformation Mechanisms
Division
Head: Prof. Dr. Frank Rösl
Viral Transformation Mechanisms (F030)
German Cancer Research Center
Im Neuenheimer Feld 280
69120 Heidelberg
Phone: +49 6221 42 4900
[email protected]
Mitochondria staining in primary
keratinocytes (orange).
Courtesy of Dr. B. Rincon Orozco (F030)
1. Mechanisms of human papillomavirus
(HPV)-induced carcinogenesis: Here we are
investigating how transcription and viral RNA
splicing of high-risk HPV is regulated during
the different steps towards malignant transformation. Another focus is the function of
epigenetic mechanisms (e.g. de novo methylation, nucleosomal organisation, micro-RNAs)
in HPV-positive cells and their impact on viralhost interaction during persistence.
2. Immunological surveillance: In this context,
we are studying the interferon/chemokine
pathway to understand the innate response
against viral and bacterial infections. Moreover, with respect to the role of inflammation
in cancer, we are examining the function of
individual HPV oncoproteins on the NALP3 inflammasome.
3. A natural rodent model system for papillomavirus (PV)-induced skin cancer: In this
project we study the whole infection pathway,
starting from primary infection till the final
manifestation of a skin tumor in molecular
and serological terms. We have also developed
a “virus-like particle” (VLP) based vaccine to
prevent PV-induced skin lesions. This vaccine is
efficient both under normal and immunocomprimised conditions and may provide the basis
for the clinical development of potent immunization strategies against cutaneous HPV infections and HPV-induced tumors, especially in
patients awaiting organ transplantation.
4. Virus-Cell Interactome: Considering a cell as
a functional regulatory network, tumorviruses
always attack central hubs to overcome intracellular surveillance. It is therefore necessary
to understand these viral-host interactions
using both approaches of systems biology and
high-throughput strategies. Particularly potential co-infections (e.g. with bacteria), their
communication pathways and cross-talks are
under investigation.
already mapped the regulatory region of the
LKB1 tumor suppressor gene, a central master
kinase that controls the intracellular energy
status. This gene is found to be dysregulated in
HPV-positive cells. We have also dissected the
mechanism whereby tumor cells sense their
own metabolism. We will further analyse the
innate immune response under hypoxic and
energy-deprived conditions.
2. Cellular escape mechanisms: This study aims
to understand the spatial and temporal interaction of immunological effector cells of the
innate defence system with non-tumorigenic
HPV-positive cells, in direct comparison with
their tumorigenic counterparts in immunocompromized animals. In addition, we design
experiments that allow the characterization of
genes and intracellular regulatory pathways in
transplanted HPV-positive cells responsible for
tumor suppression.
3. Resistance mechanisms: Cancer cells are
robust and highly adaptive against various
therapeutic approaches. Although most of the
tumor mass can be eradicated in vivo and in
vitro, there are still cells which survive. Whether these represent cancer stem cells will be
studied in further detail.
ESSENTIAL PUBLICATIONS:
(1.) Rincon-Orozco B. et al. (2009). Epigenetic silencing
of interferon-κ in human papillomavirus type 16 positive cells. Cancer Research, 69, 8718–8725.
(2.) Rosenberger S.J. et al. (2010). Alternative splicing
of HPV16 E6/E6* early mRNA is coupled to EGF-signalling via Erk activation. Proc. Natl. Acad Sci. U.S.A.,
107, 7006–7011.
(3.) Lützner N. et al. (2012). FOXO3 is a Glucocorticoid
Receptor Target Gene and Regulates LKB1 and FOXO3
Expression Dependent on Intracellular Energy Levels Via a Positive Autoregulatory Feedback Loop. PLoS
One. 7: e42166.
(4.) Niebler M. et al. (2013). Post-Translational Control
of IL-1β via the Human Papillomavirus Type 16 E6 On-
Future Outlook:
Beside the current projects which will be followed up in greater detail, we will focus our
future interest on the following topics:
1. Metabolism and cancer: Here we will especially determine the function of the viral oncoproteins on the metabolic pathway. We have
114
Research Program
coprotein: A Novel Mechanism of Innate Immune Escape Mediated by the E3-Ubiquitin Ligase E6-AP and
p53. PLoS Pathog. Aug;9(8):e1003536
Infection and Cancer
Characterization of Tumorviruses
Division
Head: Prof. Dr. Ethel-Michele de Villiers
It has not been possible to associate the ubiquitous TT viruses to a specific disease entity, despite initial intensive worldwide investigation.
We conducted our investigations along several
lines in order to address this problem: Serum
samples and biopsies from healthy individuals,
as well as from patients with multiple sclerosis, rheumatoid arthritis, colon carcinoma,
leukemia and lymphoma were analyzed for
the presence of TT virus DNA. Although TT virus DNA was present in the majority of these
samples, we demonstrated the existence of
additional intragenomic rearranged viral molecules: one comprising replication-defective and
the other replication-competent episomes. The
latter consisted of as little as 10% of the originating full-length TT virus genome and was
termed µTTV. We developed an in vitro replication system for these viruses in which we confirmed the formation and existence of µTTV
molecules, along with the replication of the respective full-length genomes. Intragenomic rearranged TT molecules, as well as in vitro transcripts revealed new open reading frames of
which the putative proteins shared similarities
to signature motifs present in cellular proteins
involved in autoimmune diseases. The highly
conserved region (71 bp) of TT viruses harboring the origin of replication was demonstrated
in a spectrum of cell lines. Long distance PCRamplification based on this region led to the
identification of circular chimeric molecules
comprising TT virus sequences combined with
cellular sequences. A large series 0f bovine
sera was analyzed for TT sequences.
Future Outlook:
Proteins expressed by TT viral and subviral genomes are characterized and tested for a possible role in “molecular mimicry“ through their
cross-reaction against antibodies involved in
autoimmune diseases. The mechanism underlying the origin and function of cellular-TT
virus chimeric molecules is being investigated.
Specificity of the chimeric recombinant molecules for certain types of tumors and autoimmune diseases will be investigated. This may
then, in addition, lead to their development
Research at DKFZ 2014
and use as diagnostic markers. The origin and
function of an unusual pattern of TT virus sequences identified in bovine serum samples
will be analyzed, as well as possible transmission of TT virus originating from cattle (via serum, saliva and milk) to humans. An intensive
search for putative new viruses involved in
tumorigenesis is continuing, with transmission from cattle to humans being the main
focus. Full-length genomes of newly identified
TT virus are being isolated and characterized
from serum samples from leukemia patients.
Development of chimeric constructs for use as
extra chromosomal vectors poses an important challenge.
ESSENTIAL PUBLICATIONS:
(1.) de Villiers E.M. et al. (2011). The diversity of Torque
teno viruses: In vitro replication leads to the formation of additional replication-competent subviral
Characterization of Tumorviruses (F070)
Molecules. J Virol, 85, 7284–7295.
German Cancer Research Center
(2.) zur Hausen H. (2012). Red meat consumption and
cancer: Reasons to suspect involvement of bovine in-
Im Neuenheimer Feld 280
fectious factors in colorectal cancer. Int J Cancer, 130,
69120 Heidelberg
2475–2483.
Phone: +49 6221 42 4655
(3.) de Villiers E.-M. et al. (2009). Intragenomic rearrangement in TT viruses: a possible role in the patho-
[email protected]
genesis of disease. Curr. Top. Microbiol. Immunol., 331,
91–107.
(4.) de Villiers E-M. (2013). Cross-roads in the classification of papillomaviruses. Virology, 445, 2–10.
Mechanisms under
investigation for a role
of TT viruses in the
pathogenesis of disease
115
Infection and Cancer
Pathogenesis of Virus Associated Tumors
Division
Head: Prof. Dr. Dr. Henri-Jacques Delecluse
Pathogenesis of Virus Associated Tumors
(F100)
German Cancer Research Center
Im Neuenheimer Feld 280
69120 Heidelberg
Phone: +49 6221 42 4870
The Epstein-Barr virus is etiologically linked
with 2% of all malignant tumors worldwide.
Hence, a very substantial number of cancers
could be prevented by vaccination against this
virus. Our research interests are focused on
the molecular mechanisms that allow multiplication, infection and ultimately, malignant
transformation of B cells and epithelial cells.
The large size of the viral genome precludes
the use of conventional cloning techniques;
instead we have developed a genetic system
that allows modification of every single base
pair within the viral genome. Over the years
we have used this technology to construct a
large panel of viral mutants that lack genes
involved in multiple virus functions. More recently, we have focused our attention on viral
non-coding RNAs, such as the first described
v-snoRNA1 or the BHRF1 microRNA cluster. A
virus that lacks all three members of this cluster displays a reduced propensity to transform
B lymphocytes. Another avenue of research
is the study of EBV interactions with primary
epithelial cells. Although the virus mainly replicates in these cells, they also express the viral
oncogene LMP1, suggesting links between between virus replication and epithelial transformation. We have also generated mutants that
could be potentially used as vaccines. Indeed,
these produce large amounts of viral DNA-free
virus-like particles (VLPs). These particles elicit
a strong immune response, yet have lost any
pathogenic potential.
Future Outlook:
Future projects aim at pursuing the genetic
analysis of EBV functions. In particular, we
intend to identify the members of the BHRF1
miRNA cluster responsible for the phenotypic
traits observed in the triple deletion mutant.
We also intend to expand our projects on the
molecular interactions between EBV and epithelial cells.
ESSENTIAL PUBLICATIONS:
(1.) Feederle R. et al. (2009). The Epstein-Barr virus alkaline exonuclease BGLF5 serves pleiotropic functions in virus replication. J Virol., 83, 4952–4962.
(2.) Hutzinger R. et al. (2009). Expression and processing of a small nucleolar RNA from the Epstein-Barr virus genome. PLoS Pathog., 5(8):e1000547.
(3.) Busse C. et al. (2010). Epstein-Barr viruses that express a CD21 antibody provide evidence that gp350’s
functions extend beyond B-cell surface binding.
J Virol., 84, 1139–1147.
(4.) Feederle R. et al. (2011). A Viral microRNA cluster
strongly potentiates the transforming properties of a
Human Herpesvirus. PLoS Pathog, 7(2): e1001294.
[email protected]
Primary squamous epithelial cells
infected with a recombinant EpsteinBarr virus tagged with a GFP gene.
116
Research Program
Infection and Cancer
Immunotherapy and -prevention
Junior Research Group
Head: PD Dr. Dr. Angelika Riemer
At least 20% of human malignancies are
caused by consequences of persistent infections. Cancers caused by infectious agents
(e.g. human papillomavirus – HPV) are attractive targets for cancer vaccination approaches, as they provide the opportunity to target
antigens that are immunologically non-self.
Vaccination can be prophylactic, inducing antibodies that prevent infection, or therapeutic,
stimulating the cellular immune system into
eradicating established disease. Prophylactic immunization against HPV has become
the paradigm for cancer immunoprevention.
Unfortunately, current HPV vaccines have no
therapeutic effect on existing infections. The
aim of therapeutic vaccination is to stimulate
the immune system into recognizing and destroying malignant cells. Cytotoxic T cells (CTL)
kill infected cells after recognizing bits of viral
proteins, so-called epitopes, which are presented on human leukocyte antigen (HLA) molecules on the cell surface. There are thousands
of different HLA types, all presenting different
epitopes. As every human being has a different set of HLA molecules, epitopes for all major
HLA groups need to be defined. The overall
aim of this group is to generate a therapeutic
cancer vaccine against HPV-induced malignancies that is applicable to everyone, regardless
of a person’s HLA type. We are currently working on the precise identification of which HPV
epitopes are present on tumor cells using a
specialized mass spectrometry (MS) approach.
gate differences in the inflammatory status
of early HPV-induced lesions between people
who mount effective immune responses and
those who do not. Since T helper cells are also
crucially involved in HPV clearance, another
project deals with the identification of naturally processed promiscuous HPV-derived HLAclass-II epitopes. The inclusion of such epitopes
in therapeutic vaccine formulations is likely
to enhance their efficacy. Future aims are to
examine various vaccine delivery and adjuvant
formulations. All these studies will contribute to an optimal formulation of a therapeutic vaccine, aiming at the effective induction
of adaptive immune responses in persistently
HPV-infected patients. The developed technology could then be applied to more high-risk
HPV types, but also to low-risk types which are
causing significant morbidity. If this approach
using an epitope-specific, yet widely applicable, therapeutic vaccine is successful, it may be
further developed into a platform technology
against other malignancies. Insights gained
during this process may be used in the further
development of cancer vaccinology.
Immunotherapy and Prevention (F130)
German Cancer Research Center
Im Neuenheimer Feld 280
ESSENTIAL PUBLICATIONS:
69120 Heidelberg
(1.) Riemer A.B. et al. (2010). A conserved E7-derived
Phone: +49 6221 42 3820
CTL epitope expressed on human papillomavirus-16
transformed HLA-A2+ human epithelial cancers.
[email protected]
J. Biol. Chem., 285, 29608–29622.
(2.) Anderson K.S. et al. (2011). Impaired tumor antigen processing by immunoproteasome-expressing
CD40-activated B cells and dendritic cells. Cancer Im-
Future Outlook:
As nearly every sexually active individual acquires a high-risk HPV infection during their
lifetime, but only 1-2% develop persistent
infection, there must be differences in the induction of effective immune responses. It has
been shown that local inflammatory cytokines
are needed for the generation of anti-HPV effector T cells. We therefore plan to investi-
munol. Immunother., 60, 857–867.
(3.) Riemer A.B. et al. (2005). Vaccination with cetuximab mimotopes and biological properties of induced anti-EGFR antibodies. J. Natl. Cancer Inst., 97,
1663–1670.
(4.) Riemer A.B. et al. (2004). Generation of peptide
mimics of the epitope recognized by trastuzumab
on the oncogenic protein Her-2/neu. J. Immunol., 173,
394–401.
Mechanisms under
investigation for a role of TT
viruses in the pathogenesis
of disease
Research at DKFZ 2014
117
Infection and Cancer
Noroviruses
CHS Junior Research Group (in Cooperation with
Heidelberg University)
Head: Dr. Grant Hansman
Noroviruses (F150)
CHS Research Group at CellNetworks
Heidelberg University and DKFZ
German Cancer Research Center
Im Neuenheimer Feld 280
69120 Heidelberg
Phone: +49 6221 42 1520
[email protected]
Noroviruses are now known to be the dominant cause of outbreaks of gastroenteritis
around the world. Currently, there are no vaccines for noroviruses and cross-protection
from future norovirus infections is uncertain,
and it is not uncommon for re-infection with a
genetically similar strain. Although the disease
is self-limiting, symptoms can persist for days
or even weeks and transmission from personto-person is difficult to control once the outbreak has occurred.
Noroviruses are an enormous problem in
closed settings such as hospitals, nursing
homes, cruise ships and schools. Human
noroviruses are frequently associated with
food-borne outbreaks of gastroenteritis. In a
nutshell, human noroviruses are everywhere
and infect all age groups. Human noroviruses
are uncultivable, but expression of the capsid
protein in a baculovirus expression system
results in the self-assembly of virus-like particles (VLPs) that are morphologically and antigenically similar to the native virion. The X-ray
crystal structure of the VLP shows the capsid is
divided into two domains, shell and protruding
(P) domains. The P domain is further divided
into P1 and P2 subdomains, with the P1 subdomain interacting with the shell and the P2 subdomain residing on the outer surface of the
capsid and likely containing the determinants
for receptor binding and antigenicity.
The human histo-blood group antigens
(HBGAs) have been identified as potential
co-factors for norovirus. A number of crystal
structures have been determined for HBGAs
in complex with P domains. Our group plans
to express a panel of norovirus strains in order
to better understand the interactions with the
polymorphic HBGAs.
Recently, we analyzed the interaction of citrate
with GII noroviruses using X-ray crystallography and saturation transfer difference (STD)
NMR. We found that the citrate interaction
was coordinated with an almost identical set
of capsid interactions involved in recognizing the terminal HBGA fucose, the saccharide
which forms the primary conserved interaction
between HBGAs and GII noroviruses. STD NMR
showed the protruding domain to have weak
affinity for citrate, but could compete against
the soluble HBGAs for the HBGA binding site.
Our group plans to screen other candidate
drug molecules that bind and inhibit norovirus
attachment to cells.
We recently solved the cryo-EM structure of
the non-infectious GII.10 VLPs and found that
the overall capsid structure was very similar to
the murine norovirus virion, including raised
and rotated P domains. Surprisingly, for over
12 years, the prototype GI.1 human norovirus
VLP was considered a good representative for
all human norovirus capsid structures and the
same group later demonstrated this with the
structure of a GII.4 human norovirus VLP. The
analysis of the GII.10 VLP cryo-EM structure
indicated that the norovirus capsid was extremely flexible and this flexibility could be the
underlying basis for receptor binding and antibody specificity. Our group plans to determine
the structures of other human norovirus VLPs
in order to describe the extent of the structural
diversity and to better understand capsid flexibility.
ESSENTIAL PUBLICATIONS:
(1.) Hansman G.S. et al. (2012). Structural basis for
broad detection of genogroup II noroviruses by a
monoclonal antibody that binds to a site occluded in
the viral particle. J Virol., 86, 3635–3646.
(2.) Hansman G.S. et al. (2012). Structural basis for
norovirus inhibition and fucose mimicry by citrate.
J Virol., 86, 284–292.
(3.) Hansman G.S. et al. (2011). Crystal Structures of
GII.10 and GII.12 Norovirus Protruding Domains in
Complex with Histo-Blood Group Antigens Reveal
Details for a Potential Site of Vulnerability. J Virol.,
85, 6687–6701.
(4.) Ozawa K et al. (2007). Norovirus infections in
symptomatic and asymptomatic food handlers in Japan. J Clin Microbiol., 45, 3996–4005.
This Junior Research Group is generously
Schematic
representation
of norovirus
118
Research Program
supported by the Chica-and-Heinz-SchallerFoundation (CHS).
Infection and Cancer
Infection and Innate Immune Sensing Dynamics
CHS Junior Research Group (in Cooperation with
Heidelberg University)
Head: Dr. Steeve Boulant
Polarized cells have developed unique biosynthetic and sorting pathways to regulate intracellular trafficking and maintain polarity.
Our laboratory is interested in how cellular
polarity influences virus host interactions. Our
research is focused on how enteric viruses enter human polarized intestinal epithelial cells
(IECs) and how these cells respond to pathogen infection. Our model virus is reovirus, the
prototype of the Reoviradae family, which contains the medically important virus Rotavirus.
The main projects within the lab are:
Virus Entry and membrane penetration
Reovirus enters polarized cells by clathrin-mediated endocytosis after binding to the tight
junction protein Jam-A and β1 integrin. Our
goal is to characterize how viruses attach to
their receptors and whether this interaction
promotes their active uptake by the cell. Using single particle tracking approaches and
live cell microscopy, we are particularly interested in the molecular aspects that allow the
coupling of the viral particles to the endocytic
machinery.
After cellular uptake, reoviruses traffic through
the early and late endosomes. These viruses
require activation in the late endosomes to
release the replication competent core into the
cytoplasm. However, the exact mechanism of
how a non-enveloped virus is able to breach
the lipid membrane to reach the cytosol remains unclear. We are currently developing
high resolution imaging and correlative microscopy techniques to shed light on how this
process is orchestrated within the cell.
Anti-viral innate immune response
IECs constitute the primary barrier that enteric
pathogens have to pass to establish infection
originating in the gut. Indeed, despite being in
constant contact with the commensal bacterial and viral flora, IECs in physiological conditions do not generate a constant pro-inflammatory response. As such, IECs have developed
unique strategies to tolerate the commensal
microbial flora and, at the same time, to effi-
Research at DKFZ 2014
ciently protect against pathogens.
We have shown that IECs can generate a different qualitative/quantitative innate immune
response upon viral infection, depending on
where the infection originates (apical vs basolateral). Our goal is to elucidate the molecular
mechanisms that differentially regulate innate immune response in polarized epithelial
cells infected by viruses. Ultimately, we aim to
understand how the innate immune response
in the intestine is regulated to maintain colonic homeostasis. Dis-regulation of this fine
balance is responsible for gut inflammation
which leads to the development of carcinoma.
ESSENTIAL PUBLICATIONS:
(1.) Boulant et al. (2013). Similar uptake but different
trafficking and escape routes of reovirus virions and
infectious subvirion particles imaged in polarized
Madin-Darby canine kidney cells. Mol Biol Cell,
4, 1196–1207.
(2.) Boulant S. et al. (2011). Actin dynamics counteract
membrane tension during clathrin-mediated endocytosis. Nat Cell Biol, 13, 1124–1131.
(3.) Cocucci E. et al. (2012). The first five seconds in the
life of a clathrin-coated pit. Cell, 150, 495–507.
(4.) Boulant S. et al. (2011). Recruitment of cellular
Infection and Innate Immune Sensing
Dynamics (F140)
CHS Research Group at CellNetworks
Heidelberg University and DKFZ
German Cancer Research Center
clathrin to viral factories and disruption of clathrin-
Im Neuenheimer Feld 581
dependent trafficking.Traffic, 12, 1179–1195.
69120 Heidelberg
This Junior Research Group is generously
supported by the Chica-and-Heinz-Schaller-
Phone: +49 6221 42 1560
[email protected]
Foundation (CHS).
Infection of polarized human intestinal
cells (T84) by the enteric virus reovirus.
(Red): JAMA, tight junction protein and the
cellular receptor for reovirus
(Green): Reovirus viral factories
(Blue): Cell nuclei, which show a
fragmentation pattern due to apoptosis/
necrotic state induced by the virus.
119
Coordinator
Prof. Dr. Christof von Kalle
Translational Cancer
Research
The DKFZ Translational Cancer Research Program serves an important bridging function
between the DKFZ and cooperating clinical facilities at the Medical Center from bench
to bedside. The research divisions contributing to this program are primarily headed by
physician scientists. A significant number of the divisions is closely interacting with the
National Center for Tumor Diseases (NCT). NCT, the first state-of-the- art comprehensive
cancer center in Germany, was formed and built in close cooperation with the Heidelberg
University Medical School (HUMS) and German Cancer Aid. NCT provides infrastructure
and resources that integrate and support all of DKFZ’s and HUMS’s clinical and translational cancer research activities. NCT’s mission is to foster interdiscip- linary oncology for
an optimized development of current clinical therapies and to rapidly transfer scientific
knowledge into clinical applications.
The Translational Cancer Research Program addresses the theme of Precision Oncology,
combining clinical algorithms and state-of-the-art molecular profiling to create diagnostic,
therapeutic and preventive strategies precisely tailored to patients’ individual disease
requirements. This Program aims to:
•
•
•
DISCOVER molecular mechanisms of neoplastic transformation by patient-oriented
high-throughput diagnostics and stratification; examination of molecular pathways,
targets and biomarkers in tumor development and metastasis; analysis of molecular
and functional heterogeneity within tumors.
DEVELOP diagnostic markers and tests by development of small molecules in therapeutic model systems; identification of biomarkers of drug action and tumor responsiveness; examination of microenvironment and inflammatory processes; modulation
of tumor immune responses.
TREAT by validation of new drugs, vaccines and strategies; determination of outcomes
in molecularly stratified patient cohorts; elucidation of mechanisms of resistance
and recurrence in functional models; development of early-detection strategies and
population-wide screening programs.
NCT has implemented a highly innovative Precision Oncology Program (NCT POP). NCT POP
is a center-wide master strategy that coordinates all translational activities and focuses
resources towards individualized cancer medicine, including patient-oriented strategies in
genomics, proteomics, immunology, radiooncology, prevention, and early clinical development. The NCT MASTER (Molecularly Aided Stratification for Tumor Eradication) umbrella
protocol streamlines the entire diagnostic trial workflow to perform and evaluate molecular diagnostics on materials from all consenting NCT patients, with the explicit purpose of
stratifying each patient for the best treatment or trial strategy.
120
Research Program
Research at DKFZ 2014
121
Translational Cancer Research
Translational Oncology
Division
Head: Prof. Dr. Christof von Kalle
Translational Oncology (G100)
German Cancer Research Center
Im Neuenheimer Feld 460
69120 Heidelberg
Phone: +49 6221 56 6990
[email protected]
The division of Translational Oncology, lead
by Christof von Kalle, coordinates all major
aspects of creating and growing NCT and the
translational research topics of DKFZ. The research program of the department focuses
on the genetic diagnosis and modification
of stem cell populations in cancer and other
genetic diseases. Comprehensive mechanistic
analysis of clonal dominance and proprietary
high-throughput genomics are used to study
the cellular and molecular mechanisms of
disease initiation, progression and metastasis
formation of cancer initiating cells, as well as
equivalent mechanisms in leukemia, aiming
at identification of new therapeutic targets.
Molecular studies focus on mutations in inherited and acquired genetic diseases, including
cancer, and serve as the basis of virus-derived
therapeutics to treat them. This work has led
the field internationally in important aspects
of gene therapy, and has pioneered mechanistic investigations of vector integration using
state-of-the-art high-throughput genomics
and bioinformatics. The division guides the
development of the NCT Precision Oncology
Program (NCT POP), which aims to provide a
comprehensive high-throughput molecular
and cellular analysis of every patient treated
at NCT, leading to therapeutic stratification according to specific molecular and cellular targets found in their individual tumors.
Bone marrow infiltration,
as determined by
immunohistochemical
staining for CD20 (top of
panel A), was 70% before
vemurafenib treatment and
cleared with treatment. The
size of the hairy-cell leukemia
clone in the peripheral
blood, as assessed by
immunophenotyping (CD20
and CD103) (bottom of panel
A), decreased rapidly with
vemurafenib treatment.
Future Outlook:
The division of Translational Oncology will further develop its research program focus in the
field of normal and cancerous stem cell biology, insertional mutagenesis in cancer and gene
therapeutic approaches. It aims to decipher
mechanisms of tumor initiation, self-renewal,
metastasis and heterogeneity of tumor-initiating cells and of the step-wise malignant transformation in leukemogenesis. The division
drives the development of NCT Precision Oncology Program (NCT POP) that aims at stratification of cancer patients based on molecular
alterations, aimed at targeted treatment approaches and hypothesis-driven interventional
trials. Structural and functional genomics and
innovative treatment approaches target individual genetic lesions. Future clinical studies
will include real-time high-throughput clonal
monitoring of the T-lymphocyte repertoire in
immunotherapy and of gene corrected cells.
New vector systems allowing either reduced
integration efficiency (integrase-deficient
lentiviral vectors) and/or targeted integration in specific safe genomic locations (zinc
finger nucleases) are being developed. Elucidation of genomic instability and the role of
double-strand breaks in carcinogenesis are
rapidly growing direct extensions of this work.
Functional genomics studies aim at new therapeutic strategies breaking therapy resistance
in high risk chronic lymphocytic leukemia. Furthermore, second-generation measles virus for
oncolytic therapy will be tested with the objective of phase I clinical trial development.
ESSENTIAL PUBLICATIONS:
(1.) Kaeppel C. et al. (2013). A largely random AAV integration profile after LPLD gene therapy. Nat Med,
19, 889–891.
(2.) Dietrich S. et al. (2012). BRAF inhibition in refractory hairy-cell leukemia. N Engl J Med, 366, 2038–2040.
(3.) Dieter SM. et al. (2011). Distinct types of tumor-initiating cells form human colon cancer tumors and
metastases. Cell Stem Cell, 9, 357–365.
(4.) Gabriel R. et al. (2011). An unbiased genome-wide
analysis of zinc-finger nuclease specificity. Nature
Biotech, 29, 816–823.
122
Research Program
Translational Cancer Research
Applied Tumor Biology
Clinical Cooperation Unit
Head: Prof. Dr. Magnus von Knebel Doeberitz
The Clinical Cooperation Unit Applied Tumor
Biology is a clinical research cooperation unit
with the Department of Applied Tumor Biology of Heidelberg University Hospitals and is
part of the Molecular Medicine Partner Unit
of the European Molecular Biology Laboratory
(EMBL). Our major scientific interests relate to
mechanisms of genomic instability triggered
by human papillomavirus infections and DNA
mismatch repair deficiency. We aim to identify novel diagnostic markers and potential
therapeutic targets. We design and organize
clinical trials, in cooperation with several clinical partners, to validate the clinical impact of
respective markers and targets. We further
successfully established “spin off” companies
to guarantee the “clinical translation” of scientific concepts into commercially available certified products. Examples of diagnostic markers
developed by our group are p16INK4a and
the CINtec® product line used as diagnostic
markers for HPV-induced lesions in histo- and
cytopathology, that within a few years have
become the new global gold standard in the
diagnostics of HPV-associated neoplasms. We
further developed a novel immune surveillance concept for DNA mismatch repair deficient cancers that led to the development of
vaccines presently being tested in clinical trials. Current research activities of our group are
focussing further on the epigenetic regulation
of human papillomavirus infections.
ESSENTIAL PUBLICATIONS:
(1.) von Knebel Doeberitz M. et al. (2012). Biomarkers
for cervical cancer screening: the role of p16(INK4a)
to highlight transforming HPV infections. Expert Rev
Proteomics, 9 ,149–163.
(2.) Reuschenbach M. et al. (2012). Evaluation of cervical cone biopsies for coexpression of p16INK4a and
Ki-67 in epithelial cells. Int J Cancer, 130, 388–394.
(3.) Kloor M. et al. (2012). Prevalence of mismatch repair-deficient crypt foci in Lynch syndrome: a pathological study. Lancet Oncol, 13, 598–606.
(4.) Kloor M. et al. (2011). Analysis of EPCAM protein
Applied Tumor Biology (G105)
expression in diagnostics of Lynch syndrome. J Clin
German Cancer Research Center
Oncol, 29, 223–227.
Im Neuenheimer Feld 280
69120 Heidelberg
Phone: +49 6221 42 2487
[email protected]
Example for HPV transformed cells
in histology (a and c) and cytology
(b and d) specimens stained for
p16INK4a (a & c) and p16INK4a and
Ki67 (b & d). Co-expression of both
markers unequivocally indicates
transformation of these cells even
in a cytology sample. This results in
a substantially better reproducible
and more sensitive and specific
identification of HPV-associated
pre-cancer cells,thus helping
to overcome most limitations
of current cervical cancer early
detection programs.
Research at DKFZ 2014
123
Translational Cancer Research
Preventive Oncology
Division
Head: Prof. Dr. Cornelia Ulrich
Preventive Oncology (G110a)
German Cancer Research Center
Im Neuenheimer Feld 460
69120 Heidelberg
Phone: +49 6221 56 5230
[email protected]
As part of our interventions studies
among hematopoietic stemcell transplantation patients we
demonstrated that physical exercise
significantly reduced cancer-related
fatigue (Wiskemann et al. 2011, Blood).
The division of Preventive Oncology reduces
the burden of cancer by conducting cuttingedge research in three areas, (a) primary prevention (identification of risk factors and biologic mechanisms), (b) secondary prevention
(early detection and screening), and tertiary
prevention (improving clinical outcomes of
cancer patients). Using state-of-the-art methods, including coordinated -omic strategies in
high quality observational and intervention
studies, we explore molecular pathways of risk
and clinical outcome. Targets are high-impact
areas including energy balance/adipose-tissue/metabolic syndrome, inflammatory/immune-modulatory processes, and lifestyle/microbial communities. Pioneering work focuses
on genetically-targeted, personalized prevention strategies through highly effective nonsteroidal anti-inflammatory drugs.
We collaborate closely with many colleagues at
the Heidelberg University Clinic to define novel
predictive and prognostic markers among
cancer patients and to discern health behaviors with major impact on cancer prognosis. In
uniquely designed clinical trials we test exercise as an adjuvant therapy in cancer and directly translate our findings into the clinic and
population. Among other research initiatives,
we lead the interdisciplinary ColoCare Study in
Heidelberg as part of an international consortium with the Fred Hutchinson Cancer Research
Center in Seattle and the Moffitt Cancer Center
in Tampa. The study builds on a cohort of colorectal cancer patients and has as its main aim
the improvement of prognosis among colorectal
cancer patients through modifiable health behaviors as well as molecularly tailored therapies.
analysis. Our approach is interdisciplinary in
collaborating extensively with other groups
and consortia. One particularly interesting
new research area addresses the obesity epidemic, its impact on inflammatory processes
and, in consequence, on cancer development.
In a large cohort of colorectal cancer patients,
we will address this topic on multiple interrelated levels: We will investigate the influence
of gene-expression and proteome patterns
of tumor-adjacent adipose tissue on the molecular characteristics of colorectal tumors,
with a special focus on inflammation and
angiogenesis. Clinicopathological and molecular tumor characteristics are investigated
in relation to the patients’ systemic status of
inflammation and oxidative damage, and to
physiologic characteristics (e.g., amount, type,
and distribution of body fat) and to health
behaviors (e.g., exercise training/sedentariness, and sun exposure). Through these integrated, interdisciplinary investigations, we
expect to gain novel insights into molecular
pathways. By identifying in these multilevel
investigations the factors that matter most
in cancer progression, we can derive the most
effective, targeted prevention strategies.
ESSENTIAL PUBLICATIONS:
(1.) Ulrich C.M. et al. (2007). Non-steroidal anti-inflammatory drugs for cancer prevention: promise,
perils and pharmacogenetics. Nature Reviews
Cancer, 6, 130–140.
(2.) Pierce B.L. et al. (2009). Elevated biomarkers of
inflammation are associated with reduced survival among breast cancer patients. Journal of Clinical
Oncology, 27, 3437–3444.
(3.) Imayama I. et al. (2012). Effects of a caloric re-
Future Outlook:
The most important goals of our division are
to advance cancer prevention by identifying
molecular mechanisms and developing strategies for personalized cancer prevention. In
addition, we strive to develop evidence-based
guidelines on health behavior interventions
after cancer diagnosis. We apply state-of-the
art methods in epidemiologic studies, devising new strategies for the statistical pathway
124
Research Program
striction weight loss diet and exercise on inflammatory biomarkers in overweight/obese postmenopausal women: a randomized controlled trial. Cancer
Res, 72, 2314–2326.
(4.) Miller J.W. and Ulrich C.M. (2013). Folic acid and
cancer – where are we today? The Lancet, 381, 1029–
1036.
Translational Cancer Research
Cellular and Molecular Pathology
Division
Head: Prof. Dr. Hermann-Josef Gröne
The division performs research into the cellular and molecular mechanisms underlying
rejection reactions in malignant tumors and
transplanted solid organs. Rejection reactions are regularly mounted by the organism
to defend itself against tumors. Using organ
transplants as animal models we can observe
the course and characteristics of rejection under defined conditions. Our interest is focused
on monocytes/macrophages – inflammationpromoting immune cells of the recipient – and
their main target, the endothelial cells lining
the inside of the blood vessels of donor organs.
Two main groups of substances are studied
with regard to the function of monocytes/
macrophages, of endothelia and of parenchymal or tumor cells in rejection: lipid-activated
nuclear receptors and glycosphingolipids (GSL).
Our goal is to gain a better understanding of
the processes underlying tissue rejection and
to transfer these findings to tumor rejection.
This may lead to novel diagnostic methods and
treatment relating to tumor rejection. The division is also concerned with clinical surgical pathology and has established a reference center
for renal diseases. Additionally, the department provides a service for histophathology of
tissue samples, including tissues from animal
experiments. The department is funded by the
DFG (German Research Foundation) for specific
projects and is part of concerted research activities of the DFG.
tion, mainly by an effect on macrophages.
By use of specific synthetic ligands and gene
knock out mice we are analyzing the cellular
and molecular pathways by which these transcription factors influence chronic fibrosing
inflammation. Sphingolipids and glycosphingolipids: Membranes of all mammalian cells
contain - in addition to phosphoglycerolipids
and cholesterol-sphingolipids: i.e. sphingomyelins (SM) and glycosphingolipids. These sphingolipids are expressed in a cell type- and differentiation stage- specific manner. GSL influence
neuronal, metabolic and immune functions.
Interactions between glycoproteins and GSLs
are pivotal to stabilize the brain and protect it
against immune reactions. We have shown in
a cell specific ganglioside-deficient animal that
GSL are needed for an orderly differentiation
of non immune cells and T-lymphocytes. We
are currently using inducible cell specific knock
outs of GSL to further define the differentiation- and immune-activity of GSL.
ESSENTIAL PUBLICATIONS:
(1.) Jennemann R, Gröne HJ. (2013). Cell-specific in vivo
functions of glycosphingolipids: lessons from genet-
Cellular and Molecular Pathology (G130)
German Cancer Research Center
Im Neuenheimer Feld 280
69120 Heidelberg
Phone: +49 6221 42 4350
[email protected]
ic deletions of enzymes involved in glycosphingolipid
synthesis. Prog Lipid Res. 52, 231–248.
(2.) Stettner P. et al. (2013). Sulfatides are required for
renal adaptation to chronic metabolic acidosis.
Proc Natl Acad Sci U S A. 110, 9998–10003.
(3.) Nordström V. et al. (2013). Neuronal expression of
glucosylceramide synthase in central nervous system
Future Outlook:
Lipid-dependent transcription factors: Nonsteroid nuclear receptors such as retinoic acid
receptors (RARs), are activated by lipid ligands;
they have highly significant and long lasting
effects on lipid and carbohydrate metabolism
and on the immune system. We have been
able to show that RAR- and LXR-receptors can
potently inhibit chronic fibrosing inflamma-
regulates body weight and energy homeostasis. PLoS
Biol. 2013;11(3):e1001506.
(4.) Traykova-Brauch M. et al. (2008). An efficient and
versatile system for acute and chronic modulation of
renal tubular function in transgenic mice. Nat. Med.,
14, 979–984.
Neurons, isolated from hippocampus.
Neurons lacking GSLs show reduced
dendritic processes and early pruning
(right slide).
Research at DKFZ 2014
125
Translational Cancer Research
Molecular Tumor Pathology
Clinical Cooperation Unit
Head: Prof. Dr. Wilfried Roth
Molecular Tumor Pathology (G150)
German Cancer Research Center
Im Neuenheimer Feld 280
69120 Heidelberg
Phone: +49 6221 56 4174
[email protected]
Our group is located both at the DKFZ and the
Institute of Pathology at University Hospital
Heidelberg. Our cooperative unit aims at bringing together basic cancer research and clinical medicine. In this regard, the translational
research is focussed on the primary human
cancer tissue. We are specifically interested
in the molecular mechanisms of therapy resistance in malignant tumors. Defects in the
intracellular signaling cascades resulting in
cell death are responsible for the therapy resistance in many types of cancer. Our research
is focussed on the molecular mechanisms
which allow tumor cells to evade apoptotic or
non-apoptotic cell death. The identification of
these resistance mechanisms is a prerequisite
for the development of novel, effective therapy
approaches and contributes to a better understanding of the molecular basis of therapy resistance in colon cancer, urological tumors, and
malignant brain tumors. The second area of
research is the identification of prognostic and
predictive tumor markers. Due to their central
biological relevance, cell death-regulating proteins are decisive for the therapy response in
cancer. Therefore, we study the expression of
cell death-regulating proteins in the primary
human cancer tissue to identify tumor markers. This predictive approach in molecular
pathology aims at the identification of biomarkers which is required for the development
of individualized therapeutic approaches for
cancer patients.
Future Outlook:
Regarding our first research area, the mechanisms of therapy resistance in cancer, we are
working on the following projects:
• Functional characterization of a novel
type of cell death: giant mitochondriaassociated cytotoxicity by the HMGB1
protein.
• Role of Bcl-2 family proteins for the resistance to cell death in colon carcinomas.
• Apoptosis resistance by the stem cell factor Notch in glioblastomas.
• Regulation of cell death by miRNAs.
• Mechanisms of therapy resistance in renal cell carcinomas mediated by defects
in the mTOR signaling pathway.
• Functional relevance of alternative types
of cell death for therapy resistance: necrosis and autophagy.
Regarding our second research area, the identification of tumor markers, we will focus on the
following projects:
• Prognostic relevance of death ligands and
death receptors in renal cancer.
• Expression and prognostic relevance of
apoptosis-regulating proteins in colon
cancer.
• G proteins as novel biomarkers in malignant brain tumors.
ESSENTIAL PUBLICATIONS:
(1.) Gdynia G. et al. (2010). Danger signaling protein
HMGB1 induces a distinct form of cell death accompanied by formation of giant mitochondria. Cancer
Research, 70, 8558–8568.
(2.) Böck B.C. et al. (2010). The PEA-15 protein regulates
autophagy via activation of JNK. J Biol Chem, 285,
21644–21654.
(3.) Macher-Goeppinger S. et al. (2009). Prognostic
value of Tumor Necrosis Factor-Related Apoptosis-inducing ligand (TRAIL) and TRAIL receptors in renal cell
cancer. Clinical Cancer Research, 15, 650–659.
(4.) Tagscherer K.E. et al. (2008). Apoptosis-based
Electron microscopy of a cancer cell:
Formation of giant mitochondria during the
process of a specialized form of cell death.
126
Research Program
treatment of glioblastoma with ABT-737, a novel
small molecule inhibitor of Bcl-2 family proteins.
Oncogene, 27, 6646–6656.
Translational Cancer Research
Dermato-Oncology
Clinical Cooperation Unit
Head: Prof. Dr. Jochen Utikal
The Clinical Cooperation Unit “Dermato-Oncology” is engaged in the prevention, diagnosis,
and therapy of skin tumors. Research results
obtained are transferred directly into clinical
practice. The main focus is malignant melanoma, a tumor that originates from the pigment
cells of the skin. The Clinical Cooperation Unit
“Dermato-Oncology” conducts several translational research projects including different
Phase I–IV clinical trials with innovative melanoma therapies such as BRAF/MEK inhibition
and anti-PD1 therapy.
Basic science researchers at the department
work on similarities of tumor cells such as melanoma cells and embryonic stem cells; on immunosuppressive mechanisms in tumors; on
chronic inflammation and its impact on tumor
development and progression; and on novel
biomarkers for malignant melanoma.
The Clinical Cooperation Unit Dermato-Oncology is part of the Research Program Translational Cancer Research and is associated with
the Program Tumor Immunology.
Future Outlook:
The Clinical Cooperation Unit Dermato-Oncology will be engaged in the prevention, diagnosis and therapy of skin tumors, such as the
malignant melanoma. Also, different clinical
trials to improve the therapeutic options for
the treatment of this tumor type will be conducted. In future an additional major focus
of the department will be stem cell research.
Embryonic stem cells and tumor cells have
many aspects in common, including immortal cell growth and the potential of forming
tumors. Furthermore, melanoma cells can be
transformed via ectopic expression of these
transcription factors into a pluripotent state.
The mechanism behind this plasticity will be
studied. In addition, we plan to study the reaction of the immune system towards the plasticity of different melanoma subpopulations.
Accordingly, immune cells, such as myeloid
derived suppressor cells, regulatory T cells and
tolerogenic dendritic cells, will be studied in
human melanoma lesions and our ret transgenic mouse melanoma model. Metabolic and
signaling pathways in immunosuppressive
cells, responsible for the production of mediators blocking anti-tumor activity of effector
and memory T cells, will also be examined.
Dermato-Oncology (G300)
German Cancer Research Center
Im Neuenheimer Feld 280
69120 Heidelberg
Phone: +49 621 383 4461
[email protected]
ESSENTIAL PUBLICATIONS:
(1.) Utikal J. et al. (2009). Immortalization eliminates a
roadblock during the reprogramming of somatic cells
into iPS cells. Nature., 460, 1145–1148.
(2.) Utikal J. et al. (2009). Sox2 is dispensable for the
reprogramming of melanocytes and melanoma cells
into induced pluripotent stem cells. J Cell Sci., 122,
3502–3510.
(3.) Meyer C. et al. (2011). Chronic inflammation promotes myeloid-derived suppressor cell activation
blocking antitumor immunity in transgenic mouse
melanoma model. Proc Natl Acad Sci U S A.; 108, 17111–
17116.
(4.) Flaherty K.T. et al. (2012). Improved Survival with
MEK Inhibition in BRAF-Mutated Melanoma.
N Engl J Med, 367, 107–114.
Primary malignant melanoma
Research at DKFZ 2014
127
Translational Cancer Research
Molecular Hematology/Oncology
Clinical Cooperation Unit
Head: Prof. Dr. Alwin Krämer
Molecular Hematology/Oncology (G330)
German Cancer Research Center
Im Neuenheimer Feld 280
69120 Heidelberg
Phone: +49 6221 42 1440
[email protected]
128
Numerical and structural chromosomal alterations and chromosomal instability are common features of human malignancies. In addition, intratumoral genetic heterogeneity and
clonal evolution are major contributors to disease progression, relapse and treatment resistance. Despite chromosomal instability appears
to be a major cause of tumor development and
progression, only little is known about its molecular origins. The Clinical Cooperation Unit
Molecular Hematology/Oncology is studying the molecular mechanisms responsible
for the induction of chromosomal instability
and clonal evolution in malignant neoplasias. One reseach topic focuses on causes and
consequences of amplified centrosomes – the
spindle pole organizers responsible for correct
chromosome segregation during mitosis – in
human malignancies. Another current topic
centers around whole-genome sequencing approaches, aiming at the identification of mutations responsible for chromosomal instability
in human acute myeloid leukemias with complex aberrant karyotypes and extremely poor
prognosis.
and induces myeloid leukemias via amplification of centrosomes. In collaboration with the
Schiebel group from ZMBH it was shown that
EGFR signaling impacts on centrosome separation and thereby mitotic progression and rates
of chromosome missegregation. In addition,
whole-genome siRNA screening enabled the
group to identify the mechanisms leading to
clustering of supernumerary centrosomes into
two functional spindle poles in cancer cells
and thereafter to target centrosomal clustering as a novel anti-cancer strategy. Small
molecule screening led to the identification of
compounds that inhibit centrosomal clustering and selectively kill cancer cells with supernumerary centrosomes.
Generally, the aim of the department’s research is to better understand the processes
leading to chromosomal instability and, consequently, to tumor development and progression. A further goal is to exploit the results of
this work for establishing new ways of tumor
classification and treatment.
ESSENTIAL PUBLICATIONS:
(1.) Bochtler T. et al. (2013). Clonal heterogeneity as de-
As major contributions, the department has
shown that both chromosomal instability and
clonal evolution is associated with disease
progression and poor prognosis in myeloid malignancies. Mechanistically, novel components
of the centrosome replication machinery have
been identified and mechanisms of normal
centrosome replication and centrosome amplification in cancer cells and after DNA damage have been elucidated. Also, researchers
from the group together with the Translational
Oncology department (von Kalle) have demonstrated that activation of the transcription
factor EVI1 causes chromosomal instability
Research Program
tected by metaphase karyotyping is an indicator of
poor prognosis in acute myeloid leukemia. J. Clin.
Oncol., 31, 3898–3905.
(2.) Mardin B.R. et al. (2013). EGF induced centrosome
separation promotes mitotic progression and cell
survival. Dev. Cell, 25, 229–240.
(3.) Leber B. et al. (2010). Proteins required for centrosome clustering in cancer cells. Sci. Transl. Med., 2,
33ra38.
(4.) Stein S. et al. (2010). Genomic instability and myelodysplasia with monosomy 7 consequent to EVI1 activation after gene therapy for chronic granulomatous disease. Nat. Med., 16, 198–204.
Research at DKFZ 2014
Multipolar cell division
129
Translational Cancer Research
Pediatric Oncology
Clinical Cooperation Unit
Head: Prof. Dr. Olaf Witt
The goal of the Clinical Cooperation Unit (CCU)
Pediatric Oncology is to advance the therapy
for children and adolescents with neural
cancers. Since epigenetic regulation of gene
expression is a key mechanism in stem cell
biology, differentiation and development, it is
likely that aberrant epigenetic programs play
a particular role in the genesis and progression of undifferentiated pediatric cancers.
Epigenetic programs are reversibly controlled
by an array of enzymes, including the family of
histone deacetylases (HDACs). Understanding
the molecular biology and selective targeting of individual HDACs of pediatric neural
cancer cells, including cancer stem cells, is
one of the central molecular concepts of the
CCU Pediatric Oncology. Our research groups
headed by Ina Oehme, Till Milde and Hedwig
Deubzer have identified particular HDAC family members controlling differentiation, cell
survival mechanisms, developmental pathways and self renewal in neuroblastoma and
brain tumors. As a consequence, we are now
developing small molecule compounds specifically inhibiting distinct HDACs for therapeutic
purposes in collaboration with pharma partners. A second research focus concerns the development of individualized, molecular based
targeted treatment concepts from patient to
bench and back. Finally, we translate our experimental findings into clinical practice through
development of individual targeted treatment
protocols for children and adolescents with
relapsed cancers, as well as conducting phase
I-III clinical trials in pediatric oncology based
on rational molecular concepts. To this end, we
have developed and are conducting a Phase I/
II trial with the HDAC inhibitor Vorinostat in
relapsed pediatric cancers and have initiated a
first nationwide clinical trial for personalized
oncology in paediatrics (INFORM) together
with cooperating partners from DKFZ and NCT.
Pediatric Oncology (G340)
German Cancer Research Center
Im Neuenheimer Feld 581
69120 Heidelberg
Phone: +49 6221 42 3570
[email protected]
HDAC family
members control
hallmarks of pediatric
neuronal cancers.
anchorage independent growth
HDAC8
HDACx
developmental pathways
pediatric cancer cell
HDAC8
HDAC5
HDAC9
differentiation
HDAC2
resistance to chemotherapy
HDAC1
HDACx
HDAC1
HDAC8
self renewal
proliferation
ESSENTIAL PUBLICATIONS:
(1.) Oehme I. et al. (2013). Histone deacetylase 10 promotes autophagy-mediated cell survival. Proc Natl
Acad Sci U S A.,110, E2592–601.
(2.) Lodrini M. et al. (2013). MYCN and HDAC2 cooperate to repress miR-183 signaling in neuroblastoma.
Nucleic Acids Res., 41, 6018–33.
(3.) Milde T. et al. (2011). A novel human high-risk
ependymoma stem cell model reveals the differentiation-inducing potential of the histone deacetylase inhibitor Vorinostat. Acta Neuropathol. 122, 637–650.
(4.) Milde T. et al. (2012). HDAC5 and HDAC9 in medulloblastoma: novel markers for risk stratification and
role in tumor cell growth. Clin Cancer Res. 16, 3240–
3252.
apoptosis
130
Future Outlook:
1. Drug target validation: We will define the
tumor biological function of individual
HDACs with respect to regulation of the
human acetylome and downstream pathways in pediatric neuronal cancers. To
this end, we will include primary tumor
material, cancer stem cell and animal
models in our projects. This will facilitate
the identification of potential biomarkers for treatment response prediction and
establish the basis for patient selection
in future trials involving selective HDAC
inhibitors.
2. Drug development: We will pursue the
development of selective small molecule
HDAC-inhibitors towards phase I clinical
trials. In addition, we aim for identification of synthetic lethal interacting pathways cooperating with selective HDAC inhibitors to facilitate rational combination
therapies in the future.
3. Disease models: We will extend our primary tumor model bank for pediatric neuronal cancers. We will evaluate individualized targeted treatment concepts using
primary brain tumor models and integrative genomic approaches.
4. Clinical trials: We will continue to expand
our early phase I and II clinical trial efforts
in pediatric oncology as well as conducting international phase III trials in low
grade gliomas in children.
Research Program
Translational Cancer Research
Molecular Oncology of Solid Tumors
Clinical Cooperation Unit
Head: Prof. Dr. Dr. Heike Allgayer
In general, the group under Heike Allgayer focuses on key mechanisms driving metastasis,
especially tumor-associated proteases and
micro RNAs, and their translational relevance.
They discovered major regulatory mechanisms of the urokinase receptor (u-PAR) and
resulting molecular staging models. The group
identified Cetuximab as a metastasis inhibitor,
u-PAR being a novel biomarker of Cetuximab
sensitivity. The group also implicated for the
first time the anti-malaria agent Artesunate as
a metastasis inhibitor, acting via u-PA/MMPs.
Furthermore, the group pioneered Pdcd4 in its
function as a novel metastasis suppressor by
regulating u-PAR, and as an independent prognostic marker, which they showed to be essentially downregulated in cancer by microRNA-21.
Recently, the Allgayer group extended their focus on microRNAs and metastasis. For the first
time they described microRNA-21 post-transcriptionally downregulating Pdcd4 and stimulating three different steps of the metastastic
cascade; a work currently cited more than 600
times since its publication. The group also implicated other microRNAs as novel regulators
of metastasis, e.g. miR-200c, miR-34a, or the
miR-30-family. Recently, within a DKFZ-MOST
project, they suggested a metastatically critical network of miR-21, miR-34a, Pdcd4, Src, and
PTEN. Current work suggests several novel
miRs to be significantly deregulated in a systematic profiling approach of resected colorectal patient metastasis tissue. From these, the
group functionally concluded a molecular network of miRs and their partly common targets
which all culminate in EMT-regulation, representing a metastatically critical miR-network
(in preparation for publication).
tasizing to a particular organ regardless of the
primary tumor type (“site-specific metastasis”). These projects will help us essentially to
characterize the metastatically relevant cancer
cell. Furthermore, we will continue with functional projects on novel miRs which we have
detected in resected patient metastasis tissues
and characterize those molecular targets and
pathways enabling them to act as metastasis regulators. This will be strongly supported
by head-to-head comparison with novel miRs
indicated by microRNAs implicated in zebrafish
and diverse mouse models of collaborators.
Current activities on resected inflammatory
and resulting colon cancer tissue of patients
with Morbus Crohn or ulcerative colitis will
look at miRs specifically relevant for colon
carcinogenesis and metastasis arising from a
chronic inflammatory background. Finally, in
recently funded collaborations we will screen
larger series of colorectal cancer patients prospectively for the expression of metastasisrelevant miRs identified by us, supporting the
development of novel biomarkers and targets
out of the miR metastasis field.
Finally, Heike Allgayer has just established and
coordinates a DKFZ-Metastasis Research Group
(MRG) to combine forces accelerating innovative and high-risk projects in the essential, yet
underrepresented, field of metastasis research.
The group includes essential PIs of DKFZ and
NCT.
ESSENTIAL PUBLICATIONS:
Molecular Oncology of Solid Tumors (G360)
German Cancer Research Center
Im Neuenheimer Feld 280
69120 Heidelberg
Phone: +49 621 383 2226
[email protected]
and Dept. of Experimental Surgery, Medical
Faculty Mannheim, Ruprecht Karls University
Heidelberg
(1.) Asangani I.A. et al. (2009). MicroRNA-21 (miR-21)
post-transcriptionally downregulates tumor suppressor Pdcd4 and stimulates invasion, intravasation and
metastasis in colorectal cancer. Oncogene, 27, 2128–
2136.
Future Outlook:
The group under Heike Allgayer has initiated
and rapidly advanced comparison of resected
metastases against primary tumor- and normal tissues of gastrointestinal cancer patients
using expression profiling and microRNA profiling, but also deep sequencing and especially
genome sequencing. Further tumor entities
will now be added to investigate tumor-type
independence of essential (miR-driven) molecular networks found; seeking to suggest additional molecular pathways essential for metas-
Research at DKFZ 2014
(2.) Nikolova D. et al. (2009). Cetuximab attenuates metastasis and u-PAR expression in non-small cell lung
cancer: u-PAR and E-cadherin are novel biomarkers of
cetuximab sensitivity. Cancer Res., 69, 2461–2470.
(3.) Mudduluru G. et al. (2011). Regulation of Axl receptor tyrosine kinase expression by miR-34a and
miR-199a/b in solid cancer. Oncogene, 30, 2888–2899.
(4.) Rasheed SAK. et al.(2010). First evidence that the
antimalarial drug artesunate inhibits invasion and in
vivo metastasis in lung cancer by targeting essential
extracellular proteases. Int. J. Cancer, 127, 1475–1485.
Chicken chorioallantoic membrane
(CAM) assay: Primary tumor in the
upper CAM.
131
Translational Cancer Research
Molecular Oncology of Gastrointestinal Tumors
Division
Head: Prof. Dr. Rienk Offringa
Molecular Oncology of Gastrointestinal
Tumors (G180)
German Cancer Research Center
Im Neuenheimer Feld 280
69120 Heidelberg
Phone: +49 6221 42 3140
[email protected]
The Division Molecular Oncology of Gastrointestinal Cancers was founded in 2011 with
support from the KH Bauer Foundation. The
decision to direct research efforts to pancreatic cancer was based on the urgent unmet
medical need this disease represents, with incidence and mortality rates still being almost
equal, and the fact that Heidelberg University
hosts the European Pancreas Center, one of
the world’s leading clinics for the treatment of
pancreatic cancer.
Our research aims at the implementation of
immunotherapy in conjunction with surgery,
chemotherapy and/or small molecule inhibitors. The choice for immunotherapy was inspired by recent successes with this approach
for other cancers in the clinic, as well as emerging pre-clinical evidence that redirection of immune pathways is one of the most promising
avenues towards more effective non-surgical
treatment of pancreatic cancer.
Our therapeutic strategy primarily involves
two approaches:
• Stimulation of the endogenous immune
potential, in particular in the tumor stroma, by means of agonist immunostimulatory monoclonal antibodies
• Exploitation of the most powerful mode
of immunotherapy: infusion of ex vivo engineered autologous T-lymphocytes
Patient-based research is supported by the excellent availability of patient biopsies, including the tissue that represents the interface
between tumor and immune system: tumordraining lymph nodes. Our research in mice
focuses on genetically engineered, autochthonous tumor models.
Future Outlook:
It is essential that our research does not stop
at the threshold between lab and clinic. This is
why we, together with our partners in the University Hospital and at the National Center for
Tumor Diseases (NCT) Heidelberg, are setting
up a pipeline for rationally designed clinical
trials in pancreatic cancer. Biomarker research
constitutes a pivotal aspect of this rational design, both with respect to patient stratification
and evaluation of therapy efficacy.
Our studies with agonist immunostimulatory
antibodies will involve neo-adjuvant studies in
patients with primary resectable or locally advanced disease, because this setting features a
sufficiently long time window for these drugs
to mobilize the patient’s endogenous immune
response. Moreover, this allows analysis of
treatment impact in the tumor microenvironment. These studies will be performed in the
context of the EU-funded network program
IACT (Immunostimulatory Agonist antibodies for Cancer Treatment) coordinated by our
division.
The trials involving T-cell infusion will be
staged in patients with recurrent disease after
primary tumor resection, because at this stage
a faster acting, ready-to-go army of immune
cells will be required to effectively combat the
tumor.
ESSENTIAL PUBLICATIONS:
(1.) Oliveira C.C. et al. (2010). The nonpolymorphic
MHC Qa-1b mediates CD8+ T cell surveillance of antigen-processing defects. J Exp Med, 207, 207–221.
(2.) Offringa R. (2009). Antigen choice in adoptive Tcell therapy of cancer. Curr Opin Immunol, 21,
190–199.
(3.) Bos R. et al. (2008). Balancing between antitumor
efficacy and autoimmune pathology in T-cell-mediated targeting of carcinoembryonic antigen. Cancer
Res, 68, 8446–8455.
(4.) van Hall T et al. (2006). Selective cytotoxic T-lymphocyte targeting of tumor immune escape variants.
Nat Med, 12, 417–424.
132
Research Program
T-cells
Tumor fragment
Tumor–infiltrating lymphocytes (TILs) are a good source
of tumor-reactive T-cells. Although their activity is
restrained by the tumor microenvironment, these T-cells
can be effectively re-activated and expanded in vitro, also
in the case of pancreatic ductal adenocarcinoma (see
microscopic image; I. Poschke & J. Hermes). This offers a
promising perspective for the development of adoptive
Research at DKFZ 2014T-cell therapy for this disease (see inset).
133
Translational Cancer Research
Neurooncology
Clinical Cooperation Unit
Head: Prof. Dr. Wolfgang Wick
Neurooncology (G370)
Department of Neurooncology Heidelberg
University Hospital and National Center for
Tumor Diseases Heidelberg
Im Neuenheimer Feld 400
69120 Heidelberg
Phone: +49 6221 56 7075
Fax: +49 6221 56 7554
[email protected]
The clinically oriented research focusses on
the development of diagnostic, prognostic and
predictive biomarkers in anaplastic glioma and
glioblastoma. This research is done in collaboration with the Epigenetics group at the DKFZ,
funded by the Federal Ministry of Education
and Research (BMBF) and building on two larger randomized trials, which have been coordinated from the clinical neurooncology unit. A
second focus is on unravelling the molecular
mechanisms of several targeted therapies in
glioblastoma, like the protein kinase C beta
inhibitor, enzastaurin, the mammalian target
of rapamycin inhibitor, temsirolimus and the
soluble CD95, APG101 plus the understanding
of the interaction between these therapies
and radiation. In an ongoing effort, the group
is aiming at developing normal hematopoietic
stem cells into therapeutic vehicles. The challenges and interactions here are the molecular
mechanisms of specific lesions-tropisms as
well as the implementation of a safe, clinically
useful lentiviral transduction system. With a
specific focus on vascular endothelial growth
factor receptor 2 and regulator of G protein
signaling 4, the group seeks to understand the
fundamental principles of evasive resistance
against the classical anti-angiogenic agents
and, with modification, in radiation therapy.
Ultimately, the research in the Clinical Cooperation Unit (CCU) Neurooncology should
focus on problems derived from the clinical
Neurooncology Program, with the clear aim to
translate the results back into the clinic.
tumors. Currently, one such predictive marker
for anaplastic glioma is under research. Using
a similar approach, a study cohort of elderly
patients with malignant glioma will be characterized for differential methylation patterns
compared to the standard malignant glioma in
middle-aged patients aiding the understanding of the comparatively worse prognosis.
From this and other research on targeted therapies, new molecules and ultimately, points
for intervention are to be developed. Here, the
focus is on small molecule screens and compound development. With the establishment
of a new group on multiphoton-microscopy
in the CCU, the core field of angiogenesis and
brain metastases will be strengthened. The
focus of this group is to understand the mode
of action of anti-angiogenic therapies in the
brain and to elucidate the specific properties
of cancer cells that successfully establish brain
metastases. As with other projects, the group
is strongly linked to the CCU Neuropathology
and the experimental imaging departments
at both the Head Clinic and the DKFZ. This will
be of utmost importance for the transfer of research results to the clinic.
ESSENTIAL PUBLICATIONS:
(1.) Wick W. et al. (2009). NOA-04 Randomized Phase
III Trial of Sequential Radiochemotherapy of Anaplastic Glioma With PCV or Temozolomide. J. Clin. Oncol.,
27, 5874–5880.
(2.) Wick W. et al. (2012). Temozolomide chemotherapy
alone versus radiotherapy alone for malignant astrocytoma in the elderly: the NOA-08 randomised, phase
Future Outlook:
Given a new biomarker, which optimally would
be sufficient to guide therapy decisions, this
will be characterized, developed and explored
for its potential in diseases other than brain
3 trial. Lancet Oncol. 13, 707–715.
(3.) Berger B. et al. (2010) Defective p53 antiangiogenic signaling in glioblastoma. Neuro-Oncol, 12, 894–
907.
(4.) Wick A. et al. (2011) Bevacizumab does not increase the risk of remote relapse in malignant glioma. Ann Neurol, 69, 586–592.
Blood vessel
morphology and
function imaged by in
vivo MPLSM.
134
Research Program
Translational Cancer Research
Neuropathology
Clinical Cooperation Unit
Head: Prof. Dr. Andreas von Deimling
The Clinical Cooperation Unit Neuropathology
was founded in 2007. Our research focuses on
molecular genetics of pediatric and adult tumors of the central nervous system, the function of neurofibromin, and the molecular reference analysis for brain tumor studies.
Prof. A. Korshunov examines pediatric brain
tumors in close cooperation with other groups
from the DKFZ, with a focus on medulloblastomas, pilocytic astrocytomas and ependymomas. We are participating in the International
Cancer Genome Consortium (ICGC). For adult
gliomas our main interest is in diffuse astroand oligodendroglial tumors characterized by
IDH1 mutations. Dr. D. Capper and F. Sahm are
characterizing this and other mutations and
are developing diagnostic tools for routine applications. Dr. S. Pusch and Dr. J. Balss are conducting research on the function of mutated
IDH1. The tumor syndrome neurofibromatosis
type 1 is caused by mutations of the NF1 gene
which encodes neurofibromin. Many biological
features of neurofibromin are mediated by its
RasGAP activity. However, additional functions
have been suggested. A group headed by Dr.
D. Reuss is uncovering alternative pathways of
neurofibromin to inhibit tumor cell growth.
Our molecular diagnostic program is headed
by Prof. C. Hartmann and serves multiple clinical studies by providing data such as mutational status of tumor suppressor genes or oncogenes. Our clinical partners compare these
data with clinical parameters.
Future Outlook:
We will contribute to genomic analyses of
medulloblastoma and pilocytic astrocytoma
within the ICGC: Acquisition of high-quality tumor and matched germline samples according
to ICGC guidelines; histopathological assessment; acquisition of clinical data and follow-up
information and molecular characterization of
samples using previously proposed diagnostic
and prognostic markers. In cooperation with
DKFZ partners, we have designed a conditional
knock-in mouse model for the IDH1-R132H mutation. We will attempt to create mutant IDH1
driven mouse brain tumor models. This likely
will require combination with other tumorigenic alterations such as TP53 mutations and
tissue specific expression at different times of
development.
Future tasks within the NF1 project are to verify our results from cellular models in animal
models and to extend our understanding of
potential alternative NF1 pathways. We will use
well characterized NF1 mouse models in which
mice develop multiple neurofibromas closely
resembling human disease. In our molecular
diagnostic program we attempt to meet the
growing demand from our clinical partners
within the DKFZ as well as from multicenter
studies. We are prepared to adapt our molecular diagnostic assays to the needs of individual
study protocols.
Neuropathology (G380)
German Cancer Research Center
Im Neuenheimer Feld 220
69120 Heidelberg
Phone: +49 6221 56 4650
[email protected]
ESSENTIAL PUBLICATIONS:
(1.) Balss J. et al. (2008). Analysis of the IDH1 codon
132 mutation in brain tumors. Acta Neuropathol., 116,
597–602.
(2.) Capper D. et al. (2009). Monoclonal Antibody Specific for IDH1 R132H Mutation. Acta Neuropathol., 118,
599–601.
(3.) Korshunov A. (2010). Molecular staging of intracranial ependymoma in children and adults. J. Clin.
Oncol., 28, 3182–3190.
(4.) Hartmann C. et al. (2010). Patients with IDH1 wild
type anaplastic astrocytomas exhibit worse prognosis than IDH1 mutated glioblastomas and IDH1 mutation status accounts for the unfavorable prognostic
effect of higher age: implications for classification of
gliomas. Acta Neuropathol., 120, 707–718.
Research at DKFZ 2014
Example for development of a diagnostic tool. Our
antibody H09 specifically binds to IDH1 protein
with the R132H mutation. All tumor cells impose in
a strong brown color while normal brain tissue is
stained blue and grey.
135
Translational Cancer Research
Neuroimmunology and Brain Tumor
Immunology
Clinical Cooperation Unit
Head: Prof. Dr. Michael Platten
Experimental Neuroimmunology (G160)
Department of Neurooncology
Heidelberg University Hospital
Im Neuenheimer Feld 400
D-69120 Heidelberg
Phone: +49 6221 56 7107
Fax: +49 6221 56 5935
[email protected]
A paradigmatic autoimmune disease of the
central nervous system (CNS) is multiple sclerosis. On the other hand a hallmark of intrinsic
CNS tumors is profound systemic and local immunosuppression. The cellular and molecular
mechanisms that are involved in the deregulation of CNS immunity in these diseases are
incompletely understood, but probably involve
pathways common to both: too much immune
response in multiple sclerosis and too little
immune response in brain tumors. Our group
is interested in the metabolic control of CNS
immunity and brain tumor development. The
long-term goal is to identify crucial metabolic
switches that may serve as therapeutic targets. In the past years we have identified key
steps in the catabolism of the essential amino
acid tryptophan as an endogenous mechanism, restricting unwanted immune responses.
These discoveries have led to the identification
of novel therapeutic approaches and diagnostic tools that are currently undergoing clinical
evaluation. Recently, we have identified a key
receptor of tryptophan catabolites that not
only mediates tumor-promoting host cell interactions, but also tumor cell intrinsic mechanisms to sustain tumor growth and invasiveness. These recent discoveries open a new view
of the role of tryptophan catabolism in cancer
and identify novel therapeutic targets.
probably other types of cancer, via the aryl hydrocarbon receptor (AHR) raises further questions which will be tackled in the future. This is
especially important as tryptophan catabolism
has evolved in recent years as a key metabolic pathway in cancer biology and immune
regulation, and early clinical trials in cancer
patients start to employ pharmacological inhibitors. Besides translational projects aiming
at the identification of novel drugs interfering with this pathway, future basic science
projects aim at elucidating the immunological consequences of this metabolic pathway in
multiple sclerosis and brain tumors at cellular
and molecular levels using novel transgenic
animal models. In parallel, novel vaccination
strategies for gliomas will be developed involving mutated antigens using humanized mouse
models. Based on patented work on successful clinical application, a phase I/II clinical trial
will be initiated in 2014. The long term goal is
to combine therapeutic strategies to alleviate
tumor-associated immune suppression with
vaccination approaches against novel tumor
antigens in brain tumors. The translational
projects involve the Department of Neurooncology at University Hospital Heidelberg, the
National Center for Tumor Diseases and collaborations with the Clinical Cooperation Units
Neurooncology and Neuropathology.
Future Outlook:
The discovery that TDO-derived tryptophan
catabolites (kynurenines) drives brain, and
ESSENTIAL PUBLICATIONS:
(1.) Opitz C.A. et al. (2009). Toll-like receptor engagement enhances the immunosuppressive properties
of human bone marrow-derived mesenchymal stem
cells by inducing indoleamine-2,3-dioxygenase-1 via
Brain MRI scan of mice
with brain tumors that
catabolize tryptophan
(+ TDO) compared with
tumors that do not
catabolize tryptophan
(- TDO) and do not
form large tumors.
Activation of the
immunosuppressive
AHR-program (TiPARP)
in an immune cell
(LCA) infiltrating
a tryptophan
catabolizing tumor.
136
Research Program
interferon-β and protein kinase R. Stem Cell, 27, 909–
919.
(2.) Opitz C.A. et al. (2011). An endogenous tumourpromoting ligand of the human aryl hydrocarbon receptor. Nature, 478, 197–203.
(3.) Sahm F. et al. (2013). The endogenous tryptophan
metabolite and NAD+ precursor quinolinic acid confers resistance of gliomas to oxidative stress. Cancer
Research, 73, 3225–3234.
(4.) Lanz T.V. et al. (2013). Protein kinase Cβ as a therapeutic target stabilizing blood-brain barrier disruption in experimental autoimmune encephalomyelitis.
PNAS, 110, 14735–14740.
Translational Cancer Research
Experimental Therapies for Hematologic
Malignancies
Max-Eder-Junior Research Group
Head: Dr. Marc S. Raab
Despite recent advances, most cancers of the
blood and bone marrow remain incurable.
Our group is therefore focused on understanding critical pathophysiological mechanisms of
hematologic malignancies to enable the identification of innovative therapeutic targets and
treatment strategies. Together with the Clinical Cooperation Unit Molecular Hematology/
Oncology (G330, Prof. A. Krämer), we are currently investigating the clustering of supernumerary centrosomes. This is a well-recognized
cellular process on which cancer cell growth is
dependent. We are therefore working to decipher the mechanism of centrosomal clustering
in hematologic malignancies, with a view to
the development of specific inhibitors to exploit this mechanism for therapeutic ends.
In our model disease, multiple myeloma, we
aim to discover molecular mechanisms of
the pivotal transition from its premalignant
precursor state to the active malignant stage,
as well as on the pathogenesis of refractory
disease. Here, we are focusing on the characterization of aberrant cell signaling and identification of corresponding genetic changes.
We are also interested in the evaluation of
novel agents, which inhibit cellular pathways
known to be important in myeloma pathogenesis. This work is done in collaboration with
our industry partners who provide promising
compounds for assessment in our extensive
pre-clinical models. We also participate in several national and international clinical trials,
including first-in-man applications as well as
first-in-class studies.
Future Outlook:
All our projects are aimed at the discovery of
new therapeutic targets, investigating new
treatment strategies, and ultimately, improving
patient outcome. Our group has three major
goals:
• Develop novel therapeutic approaches
based on centrosomal clustering: We aim
to further develop our first lead compound towards clinical application and to
screen for novel inhibitors of centrosomal
clustering.
• Discover key events in myeloma pathogenesis: We specifically focus on refractory disease with the aim to identify
novel targets and therapeutic avenues
that have not previously been explored,
to individualize treatment for this group
of patients with the highest unmet medical need.
• Translate small molecule therapeutics
from bench to clinical trials: This includes
the evaluation of novel agents in the preclinical setting and the initiation of early
phase clinical trials in hematologic malignancies, with a focus on personalized
therapy for multiple myeloma.
ESSENTIAL PUBLICATIONS:
Experimental Therapies for Hematologic
Malignancies (G170)
German Cancer Research Center
Im Neuenheimer Feld 280
69120 Heidelberg
Phone: +49 6221 42 1450
[email protected]
(1.) Andrulis M. et al. (2013). Targeting the BRAF V600E
mutation in multiple myeloma. Cancer Discovery, 3,
862-869.
(2.) Raab M.S. et al. (2012). GF-15, a novel inhibitor
of centrosomal clustering, suppresses tumor cell
growth in vitro and in vivo. Cancer Research, 72,
5374–5385.
(3.) Raab M.S. et al. (2009). Multiple Myeloma. Lancet,
374, 324–339.
(4.) Raab M.S. et al. (2009). Targeting PKC: A novel role
for beta-catenin in ER stress and apoptotic signaling.
Blood. 113, 1513–1521.
Multipolar mitosis of a mouse
xenograft under treatment
with a prototype inhibitor of
centrosomal clustering.
Research at DKFZ 2014
137
Translational Cancer Research
Molecular Mechanisms of Tumor Cell Invasion
CHS Junior Research Group (in Cooperation with
Heidelberg University)
Head: Dr. Björn Tews
Molecular Mechanisms of Tumor Cell Invasion
(V077)
CHS Research Group at CellNetworks
Heidelberg University and DKFZ
German Cancer Research Center
Im Neuenheimer Feld 581
69120 Heidelberg
Phone: +49 6221 42 1570
[email protected]
Glioblastoma is the most aggressive brain tumor with a poor prognosis, reflected by a median patient survival of about 14 months. The
invasive nature of glioma cells mainly accounts
for their resistance to current treatment modalities, as the diffusely infiltrating tumor cells,
which evade surgical resection and survive
treatment, inevitably give rise to reoccurring
tumors.
Substantial evidence has been accumulated to
suggest that lysophospholipids are involved in
tumorigenesis; they are especially important
for therapeutic resistance of tumors by regulating tumor cell invasion. Interestingly, glioma
cells use myelin as main trajectory routes, a
substrate which normally restricts cell migration due to the presence of inhibitory proteins
such as Nogo-A. We therefore investigate
lysophospholipid G-protein coupled receptor(GPCR) signaling depending on different extracellular matrix environments.
Furthermore, we determine the molecular
basis for therapeutic sensitivity of gliomas.
Recently, we could identify a key player for increased therapeutic sensitivity, Peroxiredoxin
1 (PRDX1). Loss of PRDX1 expression frequently
occurs in 1p/19q-deleted oligodendrogliomas
and contributes to chemosensitivity of these
tumors.
Our methodological repertoire includes modulation of GPCR expression and signaling; different in vitro bioassays to study cell migration
and invasion such as organotypic slice cultures;
Real-time Cell Analyses (RTCA); time-lapse
microscopy; and in vivo mouse tumor models
(RCAS/TVA; xenografts) with transgenically labeled tumor cells enabling light sheet microscopy imaging.
Real-time Cell Analysis (RTCA) of cells
overexpressing a wildtype (wt) or inactive (mut)
form of a sphingolipid G-protein coupled receptor
which negatively regulates cell adhesion and
spreading on a CNS myelin substrate. Cell Index (CI)
decribes a relative change in electrical impedance
representing the morphological cell status. Data
shown are mean values ± SEM.
138
Research Program
Future Outlook:
Understanding the complex lysophospholipid signaling cascades in glioma subtypes
after different treatment regimens will provide important information to design new
tailored therapies for patients.
ESSENTIAL PUBLICATIONS:
(1.)Tews B. et al. (2013). Synthetic microRNA-mediated downregulation of Nogo-A in transgenic rats reveals its role as regulator of synaptic plasticity and
cognitive function. Proc Natl Acad Sci, 110, 6583–
6588.
(2.) Dittmann L.M. et al. (2011). Downregulation of
PRDX1 by promoter hypermethylation is frequent
in 1p/19q-deleted oligodendroglial tumours and increases radio- and chemosensitivity of Hs683 glioma cells in vitro. Oncogene, 31, 3409–3418.
(3.) Barbus S. et al. (2011). Differential retinoic acid signaling in tumors of long- and short-term glioblastoma survivors. J Natl Cancer Inst, 103, 598–
606.
(4.) Tews B. et al. (2007). Hypermethylation and
transcriptional downregulation of the CITED4 gene
at 1p34.2 in oligodendroglial tumours with allelic
losses on 1p and 19q. Oncogene, 26, 5010–5016.
This Junior Research Group is generously
supported by the Chica-and-Heinz-SchallerFoundation (CHS).
Translational Cancer Research
Neuropeptides
CHS Junior Research Group (in Cooperation with
Heidelberg University)
Head: Dr. Valery Grinevich
Our new laboratory will focus on the dissection of the mechanisms of neuropeptide
action in the brain, from molecular – via anatomical – to the whole organism level. We will
thus employ genetic, molecular, anatomical,
viral, optogenetic and behavioral approaches to study the effects of “addressed” axonal
release of various neuropeptides within the
distinct brain regions controlling stress and
fear responses, maternal and social behaviour.
Furthermore, our group will use animal models
of psychiatric diseases, including anxiety disorders and autism, to study the possible contribution of neuropeptides to the pathogenesis
of the respective human diseases.
ESSENTIAL PUBLICATIONS:
(1.) Knobloch S. et al. (2012). Evoked axonal oxytocin
release in the central amygdala attenuates fear response. Neuron, 73, 553–566.
(2.) Liu Y. et al. (2010). Involvement of transducer of
regulated cAMP response element-binding protein
activity CREB activity on corticotropin releasing hormone transcription. Endocrinology, 151, 109–118.
(3.) Grinevich V. et al. (2009). TgArc/Arg3.1-d4EGFP indicator mice: a versatile tool to study brain activity changes in vitro and in vivo. J. Neurosci. Meth. 184,
25–36.
(4.) Grinevich V. et al. (2005). Monosynaptic pathway
from rat vibrissa motor cortex to facial motor neurons revealed by lentivirus-based axonal tracing.
J. Neurosci., 25, 8250–8258.
This Junior Research Group is generously
supported by the Chica-and-Heinz-SchallerFoundation (CHS).
Neuropeptides (V078)
German Cancer Research Center
CHS Research Group at CellNetworks
Heidelberg University and DKFZ
Im Neuenheimer Feld 581
69120 Heidelberg
Phone: +49 6221 486 174
[email protected]
The image depicts virus-mediated cell-type specific
fluorescent labeling of hypothalamic oxytocin
neurons, as revealed by immunohistochemistry
(green: Venus, red and blue: oxytocin and
vasopressin-immunoreactivity, respectively),
and represents the targets for oxytocin axons
originating from the hypothalamic paraventricular
nucleus in the rat forebrain. Image illustrated by
Julia Kuhl.
Research at DKFZ 2014
139
Join us!
Index
A
Abdollahi, Dr. Dr. Amir 108
Allgayer, Prof. Dr. Dr. Heike 131
Angel, Prof. Dr. Peter 36
Arnold, Prof. Dr. Bernd 90
Augustin, Prof. Dr. Hellmut 42
B
Beckhove, Prof. Dr. Philipp 88
Boulant, Dr. Steeve 119
Boutros, Prof. Dr. Michael 70
Brady, Dr. Nathan 74
Brenner, Prof. Dr. Hermann 84
Bukau, Prof. Dr. Bernd 45
Burwinkel, Prof. Dr. Barbara 85
C
Cerwenka, PD Dr. Adelheid 93
D
Debus, Prof. Dr. Dr. Jürgen 102
Delecluse, Prof. Dr. Dr. Henri-Jacques 116
de Villiers, Prof. Dr. Ethel-Michele 115
Dick, PD Dr. Tobias P. 40
Diederichs, Dr. Sven 73
E
Kopka, Prof. Dr. Klaus 100
Kopp-Schneider, Prof. Dr. Annette 83
Krämer, Prof. Dr. Alwin 128
Krammer, Prof. Dr. Peter 89
Kyewski, Prof. Dr. Bruno 91
L
Ladd, Prof. Dr. Mark E. 99
Langowski, Prof. Dr. Jörg 62
Lichter, Prof. Dr. Peter 65
Liu, Dr. Hai-Kun 53
Lyko, Prof. Dr. Frank 38
M
Maier-Hein, Dr.-Ing. Lena 109
Martin-Villalba, Prof. Dr. Ana 46
Meinzer, Prof. Dr. Hans-Peter 105
Milsom, Dr. Michael 56
Monyer, Prof. Dr. Hannah 44
N
Niehrs, Prof. Dr. Christof 35
O
Offringa, Prof. Dr. Rienk 132
Oskarsson, Dr. Thordur 58
P
Edgar, Prof. Dr. Bruce 43
Eils, Prof. Dr. Roland 68
Essers, Dr. Marieke 55
Pereira, Dr. Gislene 50
Pfister, Prof. Dr. Stefan 66
Plass, Prof. Dr. Christoph 80
Platten, Prof. Dr. Michael 136
F
R
Feuerer, Dr. Markus 94
Fischer, Dr. Andreas 54
Franke, Prof. Dr. Werner W. 48
Raab, Dr. Marc S. 137
Riemer, PD Dr. Dr. Angelika 117
Rodewald, Prof. Dr. Hans-Reimer 92
Rommelaere, Prof. Dr. Jean 112
Rösli, Dr. Christoph 57
Rösl, Prof. Dr. Frank 114
Roth, Prof. Dr. Wilfried 126
G
Gissmann, Prof. Dr. Lutz 113
Grinevich, Dr. Valery 139
Gröne, Prof. Dr. Hermann-Josef 125
Grummt, Prof. Dr. Ingrid 47
H
Haberkorn, Prof. Dr. Uwe 104
Hamacher-Brady, Dr. Anne 77
Hansman, Dr. Grant 118
Hell, Prof. Dr. Stefan 106
Hemminki, Prof. Dr. Kari 82
Herzig, Prof. Dr. Stephan 41
Höfer, Prof. Dr. Thomas 69
Hofmann, Dr. Thomas G. 52
Hoheisel, Dr. Jörg D. 67
Hombauer, Dr. Hans 39
Huber, Prof Dr. Dr. Peter 103
J
S
Schlemmer, Prof. Dr. Heinz-Peter 98
Schütz, Prof. Dr. Günther 49
Stöcklin, Dr. Georg 51
T
Teleman, Dr. Aurelio 72
Tews, Dr. Björn 138
Trumpp, Prof. Dr. Andreas 34
U
Ulrich, Prof. Dr. Cornelia 124
Utikal, Prof. Dr. Jochen 127
V
Jäger, Prof. Dr. Dirk 95
Jahn, Dr. Thomas 76
Jäkel, Prof. Dr. Oliver 101
von Deimling, Prof. Dr. Andreas 135
von Engelhardt, Dr. Jakob 59
von Kalle, Prof. Dr. Christof 122
von Knebel Doeberitz, Prof. Dr. Magnus 123
K
W
Kaaks, Prof. Dr. Rudolf 81
Klingmüller, PD Dr. Ursula 63
Wick, Prof. Dr. Wolfgang 134
Wiemann, PD Dr. Stefan 64
Witt, Prof. Dr. Olaf 130
142
Imprint
Published by
German Cancer Research Center
in the Helmholtz-Association
Edited by
German Cancer Research Center
Press and Public Relations
Im Neuenheimer Feld 280
69120 Heidelberg
Germany
[email protected]
www.dkfz.de
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Dr. Stefanie Seltmann
Head of Press and Public Relations
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Selin Haritounian
Tanja Kühnle
David Männle
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Angela Browne
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Print
PRINTEC OFFSET > medienhaus >, Kassel
Picture Credits
Tobias Schwerdt (Pg. 3,6/7, 8 [third picture
from above], 9 –11, 12 [Portrait in foreground],
16, 142/143); Nicole Schuster (Pg. 8 [2nd und
4th pictures from above]); Jutta Jung (Pg. 8
[3rd picture from above], 15, 140/141); Brigitte
Engelhardt (Pg. 12/13 [background]); DKFZ LifeScience Lab (Pg. 14 [1st and 3rd picture from
above]); Nadine Querfurth (Pg. 14 [2nd picture
from above]); Dr. Martina Pötschke-Langer (Pg.
17); DKFZ Career Service (Pg. 18), Technology
Transfer (Pg. 19), Heidelberg University- Communication and Marketing (Pg. 20 above right),
University Hospital Heidelberg (Pg. 21 above
left); European Molecular Biology Laboratory
Heidelberg (Pg. 21 above middle); Max Planck
Institute for Medical Research (Pg. 21 above
right); line-of-sight - Fotolia.com (Pg. 20–21
bottom)
The images on the individual departmental
pages originate from the respective units.
© German Cancer Research Center 2014
All rights reserved.
143
German Cancer Research Center
Im Neuenheimer Feld 280
69120 Heidelberg, Germany
Phone +49 (0) 6221.42-2854
Fax +49 (0) 6221.42-2968
[email protected], www.dkfz.de
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