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Manitoba Institute of Cell Biology
The Lyonel G. Israels Laboratories
Annual Report 2009
The Manitoba Institute of Cell Biology (MICB)
gratefully acknowledges
the following organizations
for their on-going support and commitment
without which the achievements
documented in this report would not have been possible:
CancerCare Manitoba Foundation
CancerCare Manitoba
The University of Manitoba
And most especially to those who unselfishly contributed
their dollars to cancer research.
Director’s Executive Summary................................................................................2
Manitoba Institute of Cell Biology (MICB)............................................................4
MICB Budget 2007-2008........................................................................................5
MICB Advisory Board…..…...................................................................................6
MICB Principal Investigators..................................................................................9
Research Highlights...............................................................................................10
Compendium of MICB Publications (2008).........................................................36
Distribution of Impact Factors and Cited Publications.........................................40
Total Number of Grant Awards. ...........................................................................44
Patents...................................................................................................................45
Senior Investigators...............................................................................................46
Genomic Centre for Cancer Research and Diagnosis...........................................95
Manitoba Breast Cancer Research Center.…........................................................99
Mammalian Functional Genomics Centre.……..................................................102
MICB Facilities...................................................................................................104
MICB Staff..........................................................................................................106
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Changes in administrative leadership, new recruits and multiple research prizes for MICB
trainees are among the highlights of this year’s annual report from the Manitoba Institute
of Cell Biology. Importantly, our senior investigators have continued their success in
obtaining funding from various agencies to support their research and so were our trainees
in obtaining pre- and post-doctoral career awards.
Dr James Davie stepped down as Director of MICB and Provincial Director of Research
at the end of 2008 to take up the Executive Directorship of the new Manitoba Health
Research Council. We wish him well in this new and challenging endeavor. He has
graciously remained as acting Associate Director of MICB to support Dr Leigh Murphy
who has taken on the Acting Directorship of MICB as well as Dr Spencer Gibson has
been appointed Interim Provincial Director, Research CancerCare Manitoba.
We were thrilled to welcome Dr Afshin Raouf as a Senior Investigator at MICB. His
major research interest is to understand the molecular mechanisms that are involved in the
regulation of normal human mammary stem cells and how these may be altered to
produce breast tumours.
We are equally thrilled to welcome Dr Kirk McManus as a Senior Investigator at MICB.
His major research interest is the molecular mechanisms of chromosome instability and
its contribution to the development and progression of cancer particularly colon cancer.
Our Senior Scientists have been again successful in having their research funded from
both local and national agencies. Notable among our successes were MICB scientists
receiving a CFI Leading Edge Fund award, CIHR operating grants as well as several
awards from the Canadian Breast Cancer Foundation and the Prostate Cancer Foundation
of Canada.
Once again our graduate students and post-doctoral fellow trainees have done extremely
well in receiving prestigious awards from NCIC, CIHR and NSERC. As well MICB
trainees have almost cornered the market on research prizes awarded locally. Of note
Teralee Burton a PhD student with Dr Spencer Gibson won the coveted E.L.Dewry award
at the University of Manitoba research day. The success of our trainees locally, nationally
and internationally speaks highly of their quality and the superior mentorship they
receive.
2
has an established reputation not only in training high quality graduate students and
fellows but also in introducing and mentoring gifted high school students to
and research. Once again some of these students have had outstanding success in
and national science competitions this year.
year MICB’s senior investigators have published 43 research articles and acquired
million in external grant support. Our success was made possible by the strong
from CancerCare Manitoba, the CancerCare Manitoba Foundation Inc, the
of Manitoba and the Province of Manitoba.
3
The Manitoba Institute of Cell Biology (MICB) was founded in 1969 by CancerCare
Manitoba (formerly the Manitoba Cancer Treatment and Research Foundation) and
the University of Manitoba. The Institute is associated with the Faculty of Medicine
and the Health Sciences Centre and is located on the 5th, 6th and 7th floors of the
CancerCare Manitoba (CCMB) building at 675 McDermot Avenue in Winnipeg,
Manitoba, Canada.
It is dedicated to basic and translational research in biology and its relation to health,
with a primary emphasis on cancer and related diseases. Scientists study such
challenging problems as the molecular origins of cancer, the role of signal
transduction pathways in regulating cell proliferation, cell death, gene expression and
platelet function, development of markers of risk of developing invasive breast cancer,
neuronal growth and differentiation during development, programmed cell death and
the biochemical action of cancer chemotherapeutics.
Although not a degree-granting institution, the Institute plays a major role in training
scientists, whether graduate or postgraduate students, medical trainees and
investigators who come from around the world to work with our staff. Degrees are
granted through the Faculty of Medicine, Departments of Human Anatomy and Cell
Science, Biochemistry and Medical Genetics, Immunology, Pharmacology and
Therapeutics, Physiology and Medical Microbiology. Information on training
programs can be obtained from our office and the Dean of Graduate Studies.
The Institute’s web page address is:
http://www.umanitoba.ca/institutes/manitoba_institute_cell_biology/index.html
4
The Manitoba Institute of Cell Biology receives a core-operating budget from CCMF
and CCMB. Prior to being approved by CCMB Board the budget proposal is first
presented and approved by the MICB Board of Management. Currently the Institute’s
operating budget is $1.57 M. The funding covers salary support, the general operation of
the facility, visiting lectureships, equipment, maintenance and repair costs.
In the 2008-2009 fiscal year, the Institute received $2,589,598
from the following Institutions:
University of Manitoba (Administered by other Departments):
Salaries for Senior Staff
University of Manitoba (Administered by MICB):
Salaries for Senior Staff
CancerCare Manitoba
Salaries for Senior Staff
CancerCare Manitoba Foundation
Operating & Equipment/CFI Grants, Studentships & PDF Awards
Health Sciences Center
Salaries for Senior Staff
$ 776,991
$ 213,013
$
59,549
$1,472,574
$
67,471
Senior staff operate their research programs by applying for external grants.
For the year ending June 30, 2009 this funding totalled $5,894,758.
Sources of funding included:
Operating and Equipment Grants
Industry Grants and Contracts
Personnel Awards
Career Awards for Senior Staff
PDF and Student Awards
Donations
Sponsor Donations
$ 5,696,193
$ 20,213
$
$
$
$
61,618
111,125
822
4,787
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The MICB Advisory Board meets 2-3 times per year and oversees the general operation
of the Institute. CancerCare Manitoba and the University of Manitoba appoint
representatives on the Board, and jointly appoint members at large.
Members during the 2008-2009 year include:
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Dr. Janice Dodd (Chair)
Professor and Head
Department of Physiology
University of Manitoba
Mr. David Carrick
Aikins MacAulay & Thorvaldson
Dr. Leigh Murphy
Acting Director, Manitoba Institute of Cell Biology
Dr. Lesley Degner
Professor, Univeristy of Manitoba
CHSRF/CIHR Chair in Nursing Care
Helen Glass Centre for Nursing
Dr. H. S. Dhaliwal
President & CEO
CancerCare Manitoba
Dr. Garry Krepart
Chair, Gyne Oncologic Cancer Disease Site Group
CancerCare Manitoba
Dr. Dean Sandham
Dean of Medicine
University of Manitoba
Dr. Ian Smith
Institute of Biodiagnostics
National Research Council of Canada
Dr. K. Dakshinamurti
Division of Stroke and Vascular Disease
St. Boniface Hospital Research Centre
Members during 2008-2009:
Dr. Leigh Murphy
ProgramChair- Fellowship Review Panel MHRC
Member, Executive Committee MICB
Member, Manitoba Breast Tumor Bank Scientific Review Panel
Scientific Reviewer, CIHR-Endocrinology Panel
Scientific Reviewer, DOD-BCRP-Concept Grants-Endocrinology panel
Member of the College of Reviewers for the Canada Research Chairs
Scientific Reviewer, Alberta Cancer Board-Breast Cancer Research Program
Member of review panel for Winnipeg Rh Award nominees
Scientific Reviewer, Postdoctoral Fellowships-Susan Komen Foundation
Dr. Jim Davie
Scientific Reviewer, Grant Review Committee Biochemistry and Molecular
Biology Panel, CIHR
Member of NCIC Program Project Site Visit Team
Member, CFI College of Reviewers, New Opportunities Fund
Member, College of Reviewers for CRC Program
Member, MHRC Research Advisory Committee
Member, NorCOMM Scientific Advisory Board
Member, Institute of Cardiovascular Sciences Awards Committee
Member, Scientific and Medical Advisory Committee, Prostate Cancer
Research Foundation of Canada
Member, Molecular and Cellular Oncology P01 Special Emphasis Panel, US
National Cancer Institute
Member, US Congressionally Directed Medical Research Programs review
panel for the pre-doctoral traineeship award in breast cancer
Dr. David Eisenstat Scientific Reviewer, Leukemia and Lymphoma Society of Canada
Member, Scientific Advisory Committee, National Brain Tumor Society, US
Scientific Reviewer, Brain Tumor Society (USA), Low Grade Gliomas
Scientific Reviewer, NCIC, Clinical Research Fellowship panel
Member, Brain Tumor Funders Collaborative
Scientific Reviewer, Brain Tumor Funders Collaborative
Scientific Reviewer, Ontario Institute of Cancer Research (OICR) clinical &
translational operating grants committee
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Scientific Reviewer, NCIC Personnel Awards Committee
Scientific Reviewer, Leukemia and Lymphoma Society of Canada Operating
Grants Panel
Member, Scientific Advisory Board, Lymphoma Foundation of Canada
Scientific Reviewer, NIH, BMCT Study Section
Member of the NCIC-CTG, Correlative Science Hematology Committee
Scientific Reviewer, CIHR, New Investigator awards panel
Member of the NCIC Health Research Ethics Board
Manitoba Health Research Council, Research Advisory Committee
Canadian Institutes of Health Research, Reviewer for G, CPT, MCC and
GMX Panels
Member, CIHR Institute of Genetics Advisory Panel
Scientific Advisory Board Member, Genomic Quebec, Gene Regulators is
Disease
Scientific Advisory Board Member, Genomic BC, Pathogenomics of Innate
Immunity
Scientific Reviewer, BC Transgenics Centre
Israels
Chair, Simon and Sara Israels Thesis Awards Committee
Member, CCMF Project Grants and Awards Committee
Royal College of Physicians and Surgeons Specialty Committee (Nucleus)
in Pediatric Hematology/Oncology
Royal College of Physicians and Surgeons Pediatric Hematology/
Oncology Examination Committee
Scientific Reviewer, Alberta Cancer Board
Leygue
Member, Operating Grant Competition of the National Cancer Institute of
Canada (NCIC), Panel D
Member, DOD-BCRP-USAMRMC Pre and Post Doctoral Awards Panel
Basic Researchers
Dr. Leigh Murphy
Dr. James Davie
Dr. Spencer Gibson
Dr. Geoff Hicks
Dr. Sabine Mai
Dr. Kirk McManus
Dr. Michael Mowat
Dr. Etienne Leygue
Dr. Afshin Raouf
Dr. Robert Shiu
Clinicians
Dr. David Eisenstat
Dr. Don Houston
Dr. Sara Israels
Dr. James Johnston
Dr. Peter Watson
University of British Columbia
Acting Director and Margaret A. Sellers Chair and Professor
(Biochemistry and Medical Genetics)
Professor (Biochemistry and Medical Genetics)
and Acting Associate Director of MICB
Interim Provincial Director of Research of CCMB
Associate Professor (Biochemistry and Medical Genetics)
Associate Professor (Biochemistry and Medical Genetics)
Professor (Physiology)
Assistant Professor (Biochemistry and Medical Genetics)
Professor (Biochemistry and Medical Genetics)
Professor (Biochemistry and Medical Genetics)
Assistant Professor (Immunology)
Professor (Physiology)
Associate Professor (Pediatrics and Child Health) and
Director of Brain Tumor Disease Site Group
Associate Professor (Internal Medicine) and Clinician
(Medical Oncology and Haematology, CCMB)
Professor (Pediatrics and Child Health) and
Head (Section of Paediatrics)
Haematology/Oncology/BMT)
Professor (Internal Medicine), Associate Director
(Clinical ) MICB and Clinician (Medical Oncology and
Haematology, (CCMB)
Professor (Pathology and Laboratory Medicine)
Director, Tumor Tissue Repository, BC Cancer Agency
Affiliated Members
Dr. James Lau
Dr. Janice Richman-Eisenstat
Dr. Frixos Paraskevas
Dr. Asher Begleiter
Dr. Lorne Brandes
Assistant Professor (Internal Medicine)
Assistant Professor (Internal Medicine, Pharmacology
and Therapeutics)
(Manitoba Institute of Cell Biology)
Professor (Internal Medicine, Pharmacology and
Therapeutics)
Professor (Internal Medicine, and Pharmacology and
Therapeutics) and Clinician (Medical Oncology and
Haematology, CCMB)
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DR. LEIGH MUPRHY
ACTING DIRECTOR
MANITOBA INSTITUTE OF CELL BIOLOGY
Dr. Leigh Murphy was appointed as Acting Director for the Manitoba Institute of Cell
Biology for the period January 1 to December 31, 2009.
Leigh is responsible for providing leadership in all research and administrative activities
within the Manitoba Institute of Cell Biology. In addition, Leigh is responsible for
continuing the implementation of the Manitoba Institute of Cell Biology Strategic Plan.
We wish her success in her new role as Acting Director for the Manitoba Institute of Cell
Biology
CONGRATULATIONS DR. MURPHY
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DR. SPENCER GIBSON IS THE NEW
INTERIM PROVINCIAL DIRECTOR, RESEARCH
CANCERCARE MANITOBA
Dr. Spencer Gibson was appointed as Interim Provincial Director, Research, for
CancerCare Manitoba for the period April 1 to December 31, 2009. Spencer will be
responsible for providing leadership for all cancer related basic, epidemiological
behavioral, applied, translational, and clinical research activities undertaken by
CancerCare Manitoba. This will include administration of all research business within
CCMB.
Dr. Gibson will represent Manitoba at various local, provincial, national and international
committees, boards, and meetings related to cancer research. He will provide leadership
in identifying and funding opportunities for researchers from local, provincial, national
and international organizations supporting cancer research. He is also responsible for
oversight of the Clinical Investigation Office (CIO), and the Oncology Library and the
organization of the CancerCare Manitoba Foundation (CCMF) Grant Competition.
Finally, he will coordinate the translational research program to increase intra-disciplinary
cancer research in Manitoba.
We wish him success in his new role as interim Provincial Director, Research, CCMB.
CONGRATULATIONS DR. GIBSON
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An Appreciation Reception in honor of Dr. Davie
was held on December 19, 2009 for his vision,
innovation and leadership as Director of MICB and
to congratulate him on his upcoming position as
Executive Director of the Manitoba Health
Research Council.
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Dr. Afshin Raouf joined the Manitoba Institute of Cell
Biology as a Senior Scientist on March 1st, 2009.
Accumulating evidence suggests that human breast tumours are a heterogeneous
population of cells, maintained by a rare subset of cells in the tumour that have stem cell
properties suggesting that while the current therapeutic approaches may eradicate the vast
majority of cells in a tumour they might not eliminate the more relevant and rare stem
cells which slowly but eventually can regenerate new tumours. This concept also
reinforces the hypothesis that normal stem and progenitor cells are important cellular
targets in the initiation and recurrence of human breast cancer. Indeed, mutations arising
in stem cells could represent an efficient process for hijacking the regulated proliferation
and differentiation of primitive normal mammary cells. These possibilities have recently
focused much interest in investigating the molecular mechanisms that are active in normal
mammary stem cells and how these may be altered to produce tumours.
In pursuit of this goal, I have set up a research program that has 3 major objectives:
1. Identify primitive cell programs that regulate the normal function of the mammary
stem and progenitor cells.
2. Establish how the inappropriate execution of these programs causes the normal stem
cells and progenitors to acquire a cancer stem cell phenotype.
3. Determine whether this understanding can be leveraged to develop therapies against
breast cancer stem cell populations.
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Dr. Kirk McManus joined the Manitoba Institute of Cell
Biology as a Senior Scientist on June 1st, 2009.
Genome instability is widely associated with a variety tumour types including colon,
breast, ovarian and various lymphoma. Mutations that cause chromosome instability
(CIN) are now widely recognized as predisposing factors that contribute to the etiology of
tumorigenesis. One of my main goals is to identify and characterize genes that regulate
chromosome stability in humans to generate a candidate list of genes that may be
somatically mutated in CIN tumors. I have previously utilized this approach to identify
several key genes that are somatically mutated in colorectal carcinomas exhibiting CIN.
Interestingly, many of these genes encode proteins that regulate sister chromatid cohesion
and knock-down or knock-out of the genes underlies CIN. Because sister chromatid
cohesion appears to be a central theme in colon cancer, I hypothesize that this pathway
may also be aberrantly affected in other tumour types exhibiting CIN such as Hodgkin or
non-Hodgkin lymphoma. As a result I am currently undertaking a series of studies to
investigate sister-chromatid cohesion in various lymphoma cell lines.
Another major focus of my lab is to identify synthetic lethal (SL) interaction partners for
the CIN genes identified above. Conceptually, the somatic CIN mutations present in
cancer cells represent a genetic distinction from the normal surrounding tissues, that may
permit the selective targeting and killing of cancer cells. Accordingly, a major goal of my
work is to identify SL genetic interaction networks for those CIN genes identified above.
Utilizing cross-species candidate gene approaches I have begun to uncover candidate SL
interaction partners and networks that I am beginning to investigate through RNAimediated approaches coupled with high content digital imaging microscopy. Once these
interactions are confirmed and validated, chemical libraries will be screened to identify
small molecule inhibitors of the novel candidate therapeutic targets.
14
Congratulations to Dr. Jim Davie who’s published research has has been cited 220 times.
Title: Histone H4-K16 acetylation controls chromatin structure and protein interactions
Author(s): Shogren-Knaak, M; Ishii, H; Sun, JM, James Davie et al. Source:
SCIENCE Volume: 311 Issue: 5762 Pages: 844-847 Published: FEB 10 2006.
Dr. Davie’s research has also been featured on the cover of the following publications:
15
Dr. Geoffrey Hicks, Canadians for Health Research/Researcher of the Month
Deciphering the Double Helix, Winnipeg Researcher Building a Rosetta Stone for the
Human Genome
The entire human genome was mapped by the end of 2003. Technology and resources promoted
by this project have already impacted biomedical research and promise to change the way
medicine is practiced. For example, detailed genome maps have aided researchers seeking genes
associated with dozens of genetic conditions.
Geoffrey Hicks, PhD, Director of the Mammalian Functional Genomics Centre (MFGC) is linking
genes to their specific functions to help unravel their role in day-to-day activities and in disease.
Dr. Hicks is a University of Manitoba professor who is working on analyzing the genetic factors
which play a role in leukemia. His technique of disrupting the genes in mouse embryonic stem
cells and observing the results was key in understanding how different suspected genes affected
the progression of the disease.
Having demonstrated the strengths of using this targeted animal model for gene-based disease
research, Dr. Hicks and the MFGC are now involved in generating a mouse cell library that will
contain mutations in every gene in the mouse genome. This project has been specifically
identified as the next most important step following the Human Genome Project. It will advance
the understanding of how the sequence of letters (our DNA) translates into gene function,
providing a living blueprint of instruction and design. This library will be freely available to all
biomedical researchers, and will significantly impact biomedical disease-focused research
programs and biotech companies in Canada.
Dr Hicks received his PhD in Physiology at the University of Manitoba and was a National
Cancer Institute of Canada postdoctoral fellow at the Massachusetts Institute of Technology and
the Vanderbilt School of Medicine. He is a Canada Research Chair in Functional Genomics and is
the Director of the Mammalian Functional Genomics Centre, a centre in the Manitoba Institute of
Cell Biology (a joint institute between CancerCare Manitoba and the University of Manitoba) and
the Genetics Modeling Centre in the University of Manitoba. He is currently leader of the North
American Conditional Mouse Mutagenesis Project (NorCOMM), the Canadian component of The
International Knockout Mouse Project, with Janet Rossant Chief of Research, at University of
Toronto’s Hospital for Sick Children. NorCOMM is supported by Genome Prairie with funding of
$13.5 million from Genome Canada and other partners.
16
Dr. Sabine Mai received a CFI Leading Edge Fund (LEF) award for a “Three-dimensional
nanoBioMedical Imaging Node (3D-nBMIN)”. Principle users on this application are: Dr.
Jim Davie (MICB), Dr. Andrew Halayko (Physiology), Dr. Thomas Klonisch (Human
Anatomy and Cell Science), Dr. Jan Friedman (U of B), Dr. William Foulkes (McGill), and
Dr. Regen Drouin (U of Sherbrooke). The total eligible costs of this CFI project are
$3,065,159.
The proposed infrastructure will enable novel high-resolution multicolour imaging. This
will be possible due to innovative 3D structured illumination microscopy, termed “3DSIM”. 3D-SIM enables high-resolution multi-fluorescent detection and analysis of cellular
structures at sub-physical resolution (sub-Abbe) limits, i.e. beyond the physical limits
defined by the physicist Ernst Abbe (1840-1905). The current resolving power is reached at
200 nm, which is also called the “Abbe limit”. Recent discoveries, however, now allow for
imaging beyond this limit: 3D-SIM permits ‘sub-Abbe’ resolution based on structured
illumination and thus provides high spatial resolution in the cellular context. The inventors
of this technology, Schermelleh et al. (Science, 2008), have successfully analyzed the
nuclear lamina, nuclear pores and nuclear pore complexes. The thickness of the nuclear
lamina is in the range of 20-50 nm. 3D-SIM allowed them to visualize this lamin network
at an upper limit of 98 + 12 nm laterally and 229 + 22 nm axially. Confocal images showed
more than 2 fold higher values. Nuclear pore complexes resolved by 3D-SIM showed an
average of 5.6 + 3.3 foci per um2, whereas only 2.8 + 1.1 foci per um2 were detected by
confocal analysis. Electron microscopy detects 12 + 1.8 foci per um2. Thus, 3D-SIM
reaches a resolution between wide field microscopy and electron microscopy, having the
advantage of multicolor fluorescence capabilities.
This instrument is currently only available as a beta version but will be commercially
available by the end of 2009. We are excited about these new opportunities for basic and
clinical research and envision important new insights into the biology of normal and
tumour cells.
17
Open one of the massive refrigerators in Room 6058 of the CancerCare building on McDermot
Avenue and 30 seconds later an alarm will go off -- just a precaution to protect its precious
contents. Inside the giant sub -70C fridges are rows of boxes speckled with ice crystals. Peer
inside the boxes and you'll find frozen breast tumours.
Dr. Jim Davie holds a slide containing a cancer sample at CancerCare Manitoba
All the tumours have come from more than 5,000 Manitobans -- mostly women -- who
donated their cancerous tissue to science. The collection is a pivotal component of the
Manitoba Breast Cancer Research Centre, says Dr. Jim Davie, who runs the facility. "I can say
without any doubt that it is one of the best tissue banks in Canada, if not one of the best tissue
banks in the world," he says. "These freezers are backed up like you wouldn't believe. It's a
very valuable resource.“So valuable that the fridges are flanked with liquid nitrogen in case
the power goes down. If the temperature in the fridges falls below or rises above normal, an
alarm goes off and an alarm company calls someone in charge of the bank -- whether it's day
or night.
It's all part of the Manitoba Breast Cancer Research Centre. The facility opened in 2004 within
the Manitoba Institute of Cell Biology, of which Davie is director. Hidden away on the fifth
and sixth floors of the CancerCare building, the Manitoba Breast Cancer Research Centre
takes up about 6,000 square feet and employs approximately 50 researchers.
Davie says his scientists could not do their research without the breast tumour bank. Along
with helping them pinpoint new biomarkers, or signals that help diagnose breast cancer, the
tumours also help scientists determine what types of breast cancer are likely to respond to
certain treatments and whether that cancer is likely to spread.
18
Although the bank existed before the Manitoba Breast Cancer Research Centre opened its
doors, it was not as useful, considering it was spread out all over the Health Sciences Centre.
Today, the thousands of breast tumours are housed in four fridges in one room. Most have
come from live patients; fewer come from autopsies. One tumour can be divided and used in
several research studies.
Since the bank began, Davie says he and his colleagues have given over 130,000 breast
tumour sections supporting more than 90 research studies. Most were given to scientists in
Manitoba and across Canada, while 25 per cent were given to international scientists from
places including China and Germany, says Davie. "Most other banks, they just serve their inhouse research groups; they don't serve the larger community. That's what makes ours really
special," says Davie, noting that samples are given away essentially for free. Tumour banks
exist throughout Canada. The Manitoba Breast Tumour Bank is part of the Canadian Tumour
Repository Network (CTRNet), a not-for-profit network funded by the Canadian Institutes of
Health Research (CIHR). Davie says word of mouth and reputation have made the Manitoba
Breast Tumour Bank respected around the world. Though it's not the biggest, he says that it's
one of the best-managed. "It's the way that you have the tumours organized and classified”.
Michelle Parisien, project co-ordinator for the Manitoba Breast Tumour Bank, provides a tour
of a room where tumours are stored in paraffin in mini "cassette" boxes. These samples are
used in different applications than frozen material. Parisien says the samples coming into the
bank are shrinking, noting that in the past, tumours could be as big as 10 centimetres. "Now
they're one centimetre," she says. "With all the screening and mammograms, they are getting
smaller and smaller, which is great for the patient, but not so great for us.”
Dr. Georgios Skliris, a research associate at the Manitoba Breast Cancer Research Centre,
says he couldn't do his work without the breast tumour bank. Sitting at his work station,
which is covered with scattered papers and beakers, the scientist admits that his work is
tedious. It often takes years before a result is validated and considered to be groundbreaking.
"What keeps you going is maybe one day there will be a breakthrough and you will be
responsible for it, along with other people, because this cannot be done by one person.“
The Manitoba Breast Cancer Research Centre is funded by several sources, including the
Canadian Foundation of Innovation and the CancerCare Manitoba Foundation.
19
Dr. Gordon Keller, Director of the McEwen Centre for Regenerative Medicine University
Health Network, Toronto, Canada and Research Chair in Stem Cell Biology, University of
Toronto was the speaker for the DR. ARNOLD GREENBERG LECTURESHIP.
20
Dr. Geoff Hicks
Organizer/Chair
was
21
Dr. Sabine Mai was the organizer of the 10th Anniversary of the Genomic Centre
Imaging Symposium which was held on June 5, 2009 at CancerCare Manitoba.
10th Anniversary of the Genomic Centre. We celebrated the 10th anniversary of the
Genomic Centre with an Imaging Symposium that covered the previous, current and future
aspects of molecular imaging and gave an overview of current research in the area. Guest
speakers included Dr. Jeremy Squire (Queens University), Frank Somogy (Zeiss), Dr. Bart
Vermolen (Twente, The Netherlands), Dr. Verayuth Praphanphoj (Bangkok, Thailand), Dr.
Piranit Nik Kantaputra (Chiang Mai, Thailand), Dr. Hans Knecht (U of Sherbrooke, QC),
Dr. Jim Davie (MICB), Dr. Sabine Mai (MICB), as well as current trainees (Dr. Md Gollam
Sabbir, Sumit Sandhu, Landon Wark, Macoura Gadji). The event was supported by Carl
Zeiss Canada and MICB/CCMF.
22
23
The MICB Annual Retreat was held at the Lakeview Resort in Gimli
Manitoba on September 26-28, 2008.
Pediatric Oncology, Development and Cancer was the theme for the 2008
retreat. Dr. Meredith Irwin, Staff Oncologist from the Hospital for Sick Kids
in Toronto and Dr. Rod Bremner, Senior Scientist, Division of Genetics &
Development, Toronto Western Research Institute were our out of town
keynote speakers. Drs. Sara Israels, David Eisenstat, Jeff Wigle and Hao Ding
as well as students and postdoctoral fellows from the various MICB labs were
among our local speakers for the event.
24
A celebration was held in honor of Marilyn Meakin
on October 29, 2008 on the occasion of her
retirement. Marilyn was the Administrative
Assistant to the Provincial Director of Research
CancerCare Manitoba.
26
The 11th annual CancerCare Manitoba Research Day for trainees in clinical and basic
medical sciences was held April 24, 2009. Organized by the Medical Staff
Association at CancerCare Manitoba, the event is designed to promote oncology and
hematology research among trainees. The following MICB trainees received awards:
Beatriz Perez-Cadahia, a PDF with Dr. Jim Davie, won 1st prize in the Basic Science
Oral Presentation category for her presentation entitled: “Role of 14-3-3 in
transcriptional activation in response to Ras-MAPK signaling pathway”.
Elizabeth McLachlan, a PDF with Dr. Leigh Murphy, won 2nd prize in the Basic
Science Oral Presentation category for her presentation entitled: “Estrogen Receptor
beta-1 (ERƒ1) regulates expression of the inflammatory genes serpin-A1 and serpinA3 in breast cancer cells”. Please note that Dr. Ketan Badiani a Research Associate in
Dr. Murphy’s laboratory, actually gave the presentation as Dr. McLachlan was
celebration the birth of her son that morning.
Teralee Burton, a PhD student with Dr. Spencer Gibson, won 1st prize in the Basic
Science Poster Presentation category for her presentation entitled: “The Pro-Cell
Death Bcl-2 family member BNIP3 promotes Tumor Cell Survival in Glioblastoma
Multiforme (GBM)”.
Yueqin Zhou, a MSc. student with Dr. Geoff Hicks, won 2nd prize in the Basic
Science Poster Presentation category for her presentation entitled: “Identification of
RNA Targets of TLS During B Cell Development”.
Meghan Azad, a PhD student with Dr. Spencer Gibson, won 3rd prize in the Basic
Science Poster Presentation category for her presentation entitled: “Characterizing
Hypoxia-Induced Autophagy: The Role of BNIP3 and ROS in Solid Tumors”.
Golam Sabbir, a PDF with Dr. Mike Mowat, won 4th prize in the Basic Science Oral
Presentation category for his presentation entitled: “The Role of DLC-1 tumor
suppressor gene in transformation and metastasis using transgenic mouse models ”.
27
Francisco Mendoza, a Ph.D student in Dr. Spencer Gibson’s lab was this year’s recipient
of the Simon and Sarah Israels Graduate Thesis Prize. Francisco has now successfully
defended his Ph.D. and is currently a medical student at the University of Manitoba.
Teralee Burton, a Ph.D. Student in Dr. Spencer Gibson’s lab was the recipient of this
year’s Portigal award. Teralee also received the Manitoba Health Research Poster
Competition MMSF award and the Apotex Fermentation Inc. Faculty of Medicine Major
Award in Molecular Biology.
Golam Sabbir, a Postdoctoral Fellow in Dr. Mike Mowat’s lab was the recipient of this
year’s Hester award. Golam also received the Dean of Medicine MMSF award.
Mario Fonseca, a MSc Student in Dr. David Eisenstat’s lab received the Manitoba Health
Research Poster Competition Dean of Medicine award.
Meghan Azad, a Ph.D. Student in Dr. Spencer Gibson’s lab won Second Prize in the Life
Sciences Association of Manitoba “Venture Zone” pitch competition. Meghan also
received the Human Genetics Endowment Fund Graduate Student Award and the US
Department of Defence Breast Cancer Research Program - Doctoral Award.
Merrill Isenor, a MSc Student is Dr. Sabine Mai’s lab was the recipient of the Hugh J.
Anderson Graduate Award in Chemistry and the Ernst and Ingrid Bock Graduate Award.
Evan Booy, a Ph.D. Student in Dr. Spencer Gibson’s lab received the Manitoba Health
Research Poster Competition MMSF award and the CIHR Poster competition honorable
mention.
Yi Yan, a MSc Student in Dr. Leygue’s lab received an Honorable Mention in the
(Manitoba & CIHR Research Poster Competition) 2009 Canadian Student's Research
Forum.
28
Canadian National Medical Student Research Symposium
Basic/Translational Research (MD/PhD category)
Honorable Mention – Trung Le
29
PhD Thesis research presented to Sherif Louis
presented to Yueqin Zhou
30
Juliet Daet a volunteer researcher with Dr. Leigh
Murphy won best overall in the biological
category for a high school senior at the Provincial
science fair for her project entitled: 'Inhibition of
Cell Growth and Proliferation by the Polyamine
Analogue DENSPM in HER2/neu-Overexpressing
Estrogen Receptor-Positive Breast Cancer”.
The grade twelve St. Mary's Academy student
said, in a nutshell, she was looking at novel cancer
treatments and is excited about doing more
research in health care and cancer. "Eventually it
may become a therapy for cancer treatment.”
Schools’ Science Symposium
Medal and Best Overall Health and
Sciences Project
in Women’s Health Research
-Wide
-Aventis BioTalent Challenge
-Wide Science Fair - Bronze Medal
31
The Institute offers seminars on a weekly basis, which are open to all.
In the past year, guest lecturers included:
July 2, 2008
CCMB AHG Lecture Theatre
ON2134
675 McDermot Avenue
11:00 – 12:00PM
Dr. Donald White
Postdoctoral Fellow
Cancer Research UK Centre for
Cell and Molecular Biology
Institute of Cancer Research
London, United Kingdom
“Adhesion complex
signalling in the mouse”
July 10, 2008
CCMB AHG Lecture Theatre
ON2134
675 McDermot Avenue
11:00 – 12:00PM
Dr. Stuart Berger
Associate Professor
Senior Scientist
Department of Immunology
University of Toronto
“Activation Enhanced
Cell Death”
October 23, 2008
CCMB AHG Lecture Theatre
ON2134
675 McDermot Avenue
11:00 – 12:00PM
Dr. Brad Nelson
Director and Senior Scientist Of
The Deeley Research Centre
B.C. Cancer Agency
Adjunct Associate Professor
University of Victoria
“Toward Predictive and
Personalized
Immunotherapy of
Cancer”
October 29, 2008
CCMB AHG Lecture Theatre
ON2134
675 McDermot Avenue
1:00 – 2:00PM
Dr. Loydie A. Jerome- Majewska
Assistant Professor
Department of Pediatrics and
Human Genetics
McGill University, Montreal, QC
“En route to the
Placenta: Traffic stalls
between the ER and
Golgi”
November 6, 2008
CCMB AHG Lecture Theatre
ON2134-675 McDermot Ave.
11:00 – 12:00PM
Dr. Kerry Campbell
Director, Cell Culture Facility
Institute of Cancer Research
Adjunct Associate Professor
Department of Microbiology
and Immunology
Philadelphia, PA.
“Signals regulating
natural killer cell
development and
function”
Unable to attend due to family
illness
32
March 19, 2009
CCMB AHG Lecture Theatre
ON2134
675 McDermont Ave.
11:00-12:00 P.M.
Dr. Versha Banerji
Post Doctoral Fellow
Dana Farber Cancer Institute
Broad Institute of Genomics of
Harvard and MIT
“The Changing Paradigm of
Drug Discovery: Gene
Expression-based Highthroughput Screening in
Acute Myeloid Leukemia”
April 2, 2009
CCMB AHG Lecture Theatre
ON2134
675 McDermot Avenue
1:00-2:00 P.M.
Dr. Pam Del Maestro
Brain Tumor Foundation of
Canada, Canadian Cancer
Action Network, North
American Brain Tumor
Coalition
“Advocacy and the Patient
Voice”
April 2, 2009
CCMB AHG Lecture Theatre
ON2134
675 McDermot Avenue
3:00-4:00 P.M.
Dr. Roland Del Maestro
William Feindel Chair in
Neuro-Oncology
Director, Brain Tumour
Research Centre
Professor, Division of
Neurosurgery and Oncology
Montreal Neurological Institute
and Hospital McGill University
“Integrating Molecular
Information into the
Treatment of Gliomas”
April 9, 2009
CCMB AHG Lecture Theatre
ON2134
675 McDermot Ave.
11:00-12:00 P.M.
Dr. Mark Nachtigal
Assistant Professor
Dalhousie University
Department s of
Pharmacology and Medicine
Canadian Cancer Society
Research Scientist
“Investigating whether
Altered Pro-Protein
Convertase Activity may
Contribute to Ovarian
Cancer Formation”
April 20, 2009
CCMB AHG Lecture Theatre
ON2134
675 McDermot Avenue
10:30-11:30 A.M
Dr. Howard Cedar
Professor of Molecular
Biology, Hebrew University of
Jerusalem,
Department of Cellular
Biochemistry and Human
Genetics, Hadassah Medical
School, Ein Kerem, Jerusalem
“Genome wide association
studies in colorectal cancer”
33
34
April 23, 2009
CCMB AHG Lecture Theatre
ON2134
675 McDermot Avenue
3:00-4:00 P.M.
Dr. Andrew Li-jen Kung
Director of Preclinical Imaging
Assistant Professor of
Pediatrics, Dana-Farber
Cancer Institute, Boston,
Massachusetts
“Incorporation of Imaging
Endpoints in Cancer Drug
Discovery”
May 12, 2009
CCMB AHG Lecture Theatre
ON2134
675 McDermot Avenue
10:00-11:00 A.M.
Dr. Francis J Giles
Professor of Medicine
Chief, Division of Hematology
and Medical Oncology
Director, Institute for Drug
Development
Deputy Director, Cancer
Therapy & Research Centre at
the University of Texas Health
Science Centre San Antonio
“Molecular insights:
Therapeutic progress and
challenges”
May 25, 2009
CCMB AHG Lecture Theatre
ON2134
675 McDermont Ave.
2:00-3:00 P.M.
Dr. Robert Bristow
Clinician-Scientist, Ontario
Cancer Institute, Princess
Margaret Hospital
Associate Professor, Depts. Of
Radiation Oncology and
Medical Biophysics, University
of Toronto
Director, Core I – STTARR
and LEGEND Labs, Canadian
Cancer Society Research
Scientist
“Tumor Hypoxia and Genetic
Instability: An Achilles Heel
for Cancer Therapies”
May 28, 2009
CCMB AHG Lecture Theatre
ON2134
675 McDermot Avenue
11:00-12:00 P.M.
Dr. P. Jeremy Wang
Assistant Professor of
Development al Biology
Department of Animal Biology
University of Pennsylvania
Philadelphia, Pennsylvania
“Concerted Regulation of
Mitosis and Meiosis in the
Germline”
May 28, 2009
CCMB AHG Lecture Theatre
ON2134
675 McDermot Avenue
2:00-3:00 P.M.
Dr. Eftekhar Eftekharpour
Associate Neuroscientist, Spine
Program
Division of Genetics and
Development
Toronto Western Research
Institute
“Stem Cell Therapy for
Central Nervous System
Disorders: Victories of the
Past, Challenges of the
Future”
June 4, 2009
CCMB AHG Lecture Theatre
ON2134
675 McDermot Avenue
11:00-12:00 P.M.
Simon & Sara Israels
Graduate Thesis Prize
“A Balancing Act Between
Life and Death ” MEKK1
and the Apoptotic Pathway
June 23, 2009
CCMB AHG Lecture Theatre
ON2134
675 McDermot Avenue
12:00-1:00 P.M.
Dr. Arnold Greenberg
Lectureship
Francisco Mendoza
Ph.D. Medical Student
Faculty of Medicine, University
of Manitoba
“Generating functional
tissues from human
pluripotent stem cells”
Dr. Gordon Keller
Director, McEwan Centre for
Regenerative Medicine,
University Health Network,
Toronto
Canada Research Chair in Stem
Cell Biology, University of
Toronto
35
1. George P. Skliris, Brian G. Rowan , Mariam Al-Dhaheri,
Troup, Sanela Begic, Michelle Parisien, Peter H. Watson, Leigh C. Murphy.
Immunohistochemical validation of multiple phospho-specific epitopes for estrogen
receptor α (ERα) in tissue microarrays (TMA) of ERα positive human breast carcinomas.
Breast Cancer Research and Treatment 2008 Dec 23. [Epub ahead of print]
2. Gregory E. Weitsman, Wineeta Weebadda, Kanyarat Ung and Leigh C. Murphy. Reactive
oxygen species induce phosphorylation of serine 118 and 167 on estrogen receptor alpha.
Breast Cancer Research & Treatment 2008 Oct 21. [Epub ahead of print]
3. Rebecca O. Barnes, Michelle Parisien, Leigh C. Murphy, and Peter H. Watson (2008)
Influence of Evolution in Tumor Biobanking on the Interpretation of Translational
Research. Cancer Epidemiology, Biomarkers & Prevention 17:3344-50.
4. J.M. Flynn, S.D. Dimitrijevich, M. Younes, G. Skliris, L.C. Murphy, and P.R. Cammarata.
2008 Role of wild-type estrogen receptor-β in mitochondrial cytoprotection of cultured
normal male and female human lens epithelial cells. Am J Physiol Endocrinol Metab.
295(3):E637-47
5. George P. Skliris, Florent Hubé, Ionela Gheorghiu, Mark M. Mutawe, Carla Penner, Peter
H. Watson, Leigh C. Murphy, Etienne Leygue, Yvonne Myal. (2008) Expression of small
breast epithelial mucin (SBEM) protein in tissue microarrays (TMAs) of primary invasive
breast cancers. Histopathology 52:355-69
6. Kien, C.L., Peltier, C.P., Mandal, S., Davie, J.R. and Blauwiekel, R. (2008) Effects of the in
vivo supply of butyrate on histone acetylation of cecum in piglets. J. Parenter. Enteral
Nutr. 32, 51-6.
7. He, S., Dunn, K.L., Espino, P.S., Drobic, B., Li, L., Yu, J., Sun, J.M., Chen, H.Y., Pritchard,
S. and Davie, J.R. (2008) Chromatin organization and nuclear microenvironments in cancer
cells. J. Cell. Biochem. 104, 2004-15.
8. Delcuve, G.P., He, S. and Davie,J.R. (2008) Mitotic partitioning of transcription factors. J.
Cell. Biochem. 105, 1-8.
9. Li, L. and Davie, J.R. (2008) Association of Sp3 and estrogen receptor alpha with the
transcriptionally active trefoil factor 1 promoter in MCF-7 breast cancer cells. J. Cell.
Biochem. 105, 365-9.
10. Stein,G.S., Davie, J.R., Knowlton, J.R. and Zaidi, S.K. (2008) Nuclear microenvironments
and cancer. J. Cell. Biochem. 104, 1649-52.
11. Davie, J.R., He, S, Li, L., Sekhavat, A., Espino, P., Drobic, B., Dunn, K.L., Sun, J.M.,
Chen, H.Y., Yu, J., Pritchard, S. and Wang, X. (2008) Nuclear organization and chromatin
dynamics – Sp1, Sp3 and histone deacetylases. Adv Enzyme Regul. 48, 189-208.
36
12. Azad, M. B., Chen, Y and Gibson S.B. 2008 Regulation of autophagy by reactive oxygen
species (ROS): implications for cancer progression and treatment. Antioxidant and Redox
Signaling Oct 1. [Epub ahead of print]
13. Amrein L., Hernandez, T., Ferrario, C., Johnston, J., Gibson, S.B., Panasci L, and Aloyz R.
2008 Dasatinib sensitizes primary chronic lymphocytic leukemia lymphocytes to
chlorambucil and fludarabine in vitro Br. J. Haematology 143:698-706.
14. Henson, E. S., Johnston, J. B., and Gibson S. B. 2008 The role of TRAIL and its death
receptors in the treatment of hematological malignancies. Leukemia and Lymphoma
49:27-36
15. Azad M. B., Chen Y., Henson E. S., McMillian Ward E., Israels S. J., and Gibson S. B.
2008 Hypoxia induces autophagic cell death in apoptosis-competent cancer cells.
Autophagy 4:195-204
16. Chen, Y., Gibson, S. B. 2008 Mitochondria generation of reactive oxygen species is a
trigger for autophagy? Autophagy 4:246-8
17. Klionsky, DJ; Abeliovich, H; Agostinis, P, Gibson, S. B. et al. 2008 Guidelines for the use
and interpretation of assays for monitoring autophagy in higher eukaryotes. Autophagy
4:151-75
18. Hu X., Sun, J., Johnston J.B. and Gibson S.B. 2008 Lysophosphatidic acid (LPA)
induces the expression of Vascular Endothelial Growth Factor (VEGF) leading to cell
survival in hematopoietic malignancies. Cellular Signaling 20:1198-208.
19. Mendoza, F. J, Ishdorj, G., Hu, X., and Gibson, S. B. 2008 Death receptor-4 (DR4)
expression is regulated by transcription factor NF-kB in response to etoposide
treatment. Apoptosis 13:759-70
20. Ishdorj, G., Graham, B., Hu, X., Johnston, J. B., Chen, J., Fang, X., and Gibson, S. B.
2008 Lysophosphatidic acid ( LPA) protects cancer cells from HDAC inhibitor
induced apoptosis mediated by histone deacetylase (HDAC) activation. J. Biol. Chem.
283:16818-29
21. Ghavami S., Asoodeh A., Klonisch T., Halayko A. J., Gibson, S. B., Booy E., NadriManesh H., and Los M. 2008 Brevinin-2 R semi-selectively kills cancer cells by a
distinct mechanism which involves the lysosomal-mitochondrial death pathway. J.
Cell. Mol. Med. 12:1005-22
22. Skrabek, PJ; Houston, D.S. (2008) Hyperferritinemia: An Unexpected Effect of Treatment
with Danazol. Blood. 112, 1312-1312
23. Zarychanski.R, Doucette. S, Fergusson. D, Roberts. D, Houston D.S., Sharma. S, Gulati.
H, Kumar. A . (2008) Early intravenous unfractionated heparin and mortality in septic
shock. Critical Care Medicine. 36, 2973-2979.
37
24. Zarychanski, R; Houston, DS. (2008). A harmful disorder or an adaptive, beneficial
response? Canadian Medical Association Journal. 179, 449-449
25. McNicol A, Israels SJ. (2008). Beyond Hemostasis: the role of platelets in inflammation,
malignancy and infection. Cardiovasc Hematol Dis–DT. 8, 99-117.
26. Chen Y, McMillan-Ward E, Kong J, Israels SJ, Gibson SB. (2008). Oxidative stress
induces autophagic cell death independent of apoptosis in transformed and cancer cells.
Cell Death Diff. 15, 171-82.
27. Mougey V, Kuttler F, Mendis R, Mai S, Fest T. Myc box II mutated alleles promote
genomic instability by impairing c-Myc control of G2 cell cycle phase. Oncogene
accepted pending revision. 2008.
28. Silva AGdS, Sarkar R, Harizanova J, Guffei A, Mowat M, Garini Y, Mai S. Centromeres in
cell division, evolution, nuclear organization and disease. J Cell Biochem. 2008 [E pub
ahead of print].
29. Tragoolpua K, Intasai N, Kasinrerk W, Mai S, Yuan Y, Tayapiwatana C. Generation of
functional scFv intrabody to abate the expression of CD147. BMC Biotechnology 8:5.
2008.
30. Hatch,G.M., Y.Gu, F.Y.Xu, J.Cizeau, S.Neumann, J.S.Park, S.Loewen, and M.R.A.Mowat.
(2008). RhoGAP mediates ceramide activation of phosphatidylglycerolphosphate synthase
and drug response in Chinese hamster ovary cells. FASEB J. 22:269. [Meeting Abstract]
31. Goncalves Dos Santos,S.A., R.Sarkar, J.Harizanova, A.Guffei, M.Mowat, Y.Garini, and
S.Mai. (2008). Centromeres in cell division, evolution, nuclear organization and disease. J
Cell Biochem. 106: 2040-2058
32. Skliris, G.P., Leygue, E., Watson, P.H. and Murphy, L.C. (2008) Estrogen receptor alpha
negative breast cancer patients: estrogen receptor beta as a therapeutic target. J Steroid
Biochem Mol Biol, 109, 1-10.
33. Xie Y, Yang H, Miller JH, Shih DM, Hicks GG, Xie J, Shiu R (2008) Cells deficient in
oxidative DNA damage repair genes Myh and Ogg1 are sensitive to oxidants with
increased G2/M arrest and multinucleation. Carcinogenesis 29:722-728
34. Eisenstat DD. (2008) Chromatin immunoprecipitation. In: Binder MD, Hirokawa N,
Windhorst U, Hirsch MC (Eds.) Encyclopedia of Neuroscience, 4th Edition, Springer:
Heidelberg.
35. Miao P, Madec K, Gong Y, Shen H, Eisenstat D, Melanson M, Gu X, Leong C, Klowak M,
Namaka M. (2008) Axotomy-induced upregulation of Tumor Necrosis Factor-Alpha in the
dorsal root ganglia. Neurol. Res. 30, 623-631.
38
36. Wigle JT, Eisenstat DD. (2008) Homeobox genes in vertebrate
disease. Clin. Genet. 73, 212-226.
37. de Melo J, Zhou QP, Wigle JT, Eisenstat DD. (2008) Dlx2 homeobox gene transcriptional
regulation of the TrkB neurotrophin receptor expression during mouse retinal
development. Nucleic Acids Res. 36, 872-884.
38. Koul R, Dufan T, Dubey A, Schroeder G, Jones K, Vijay K, Eisenstat DD. (2008)
Imaging features of primary central nervous system lymphoma at presentation. Case
series from a regional cancer centre. Oncology Exchange 7, 24-27.
39. Johnston DL, Keene DL, Lafay-Cousin L, Steinbok P, Carret AS, Crooks B, Strother D,
Wilson B, Odame I, Eisenstat DD, Mpofu C, Zelcer S, Huang A, Bouffet E. (2008)
Supratentorial Primitive Neuroectodermal Tumors: A Canadian Pediatric Brain Tumor
Consortium Report. J. Neuro-Oncol. 86, 101-8.
40. Wigle JT, Eisenstat DD. (2008) Common signaling pathways used during development.
Ch. 21. In: Moore KL, Persaud TVN, The Developing Human, 8th Edition, Elsevier
Science: Saunders, Philadelphia.
41. Xie Y, Yang H, Pan J, Miller JH, Shih DM, Hicks GG, Xie J, Shiu RPC. (2008).
Cells deficient in oxidative DNA damage repair genes Myh and Ogg1 are sensitive to
oxidants with
increased G2/M arrest and multinucleation. Carcinogenesis,
29:2432.
42. Gulisa Turashvili, Steven McKinney, Lisa Martin, Karen A Gelmon, Peter Watson,
Norman Boyd and Samuel Aparicio. (2009) Columnar cell lesions, mammographic
density and breast cancer risk. Breast Cancer Research and Treatment. 115:561-71
43. Wang, J., Barnes, R.O., West, N.R., Olson, M., Chu, J.E., Watson, P.H.(2008) Jab1 is a
target of EGFR signalling in ER-alpha negative breast cancer. Breast Cancer Research
10 (3):R51. Eup June 6, 2008.
39
Investigator Name
Davie, J
Davie, J
Davie, J
Davie, J
Davie, J
Davie, J
Davie, J
Davie, J
Davie, J
Davie, J
Davie, J
Davie, J
Davie, J
Davie, J
Davie, J
Davie, J
Davie, J
Davie, J
Davie, J
Eisenstat, D.D.
Eisenstat, D.D.
Eisenstat, D.D.
Eisenstat, D.D.
Eisenstat, D.D.
Eisenstat, D.D.
Eisenstat, D.D.
Eisenstat, D.D.
Eisenstat, D.D.
Gibson, S.B
Gibson, S.B
Gibson, S.B
Gibson, S.B
Gibson, S.B
Gibson, S.B
Gibson, S.B
Gibson, S.B
Gibson, S.B
Gibson, S.B
40
Year
Name of Publication/Book
Published
Biochem. Cell. Biol.
2007
Biochem. Cell. Biol.
2007
Biochimica et Biophysica Acta-gene structure and expression
2006
BMC Cancer
2007
Breast Cancer Res Treat.
2006
Cancer Res.
2006
Cancer Res.
2006
Circ Res
2006
J. Biol. Chem.
2006
J. Biol. Chem.
2007
J. Cell. Biochem
2008
J. Cell. Biochem
2008
J. Cell. Biochem
2008
J. Cell. Biochem
2008
J. Cell. Sci.
2006
J. Parenter. Enteral Nutr.
2008
J. Steroid Biochem Mol Biol.
2006
Nucleic Acids Res.
2007
Science
2006
Brain
2007
Canadian Journal of Neurological Sciences
2006
Dev. Dyn.
2007
Int. J. Cancer
2006
J. Biol. Chem.
2007
J. Neuro-Oncol.
2007
J. Neuro-Oncol.
2007
Neurological Research
2007
Proc Natl Acad Sci USA
2006
Antioxid Redox Signal.
2008
Apoptosis
2006
Arthritis Rheum.
2007
Autophagy
2008
Autophagy
2008
Blood
2006
Blood
2006
Cell Death Differ.
2008
Cell Proliferat.
2007
Cellular Signalling
2006
Times
Cited
2
5
2
1
2
6
12
9
8
4
0
0
1
3
12
0
7
3
213
4
0
1
16
11
1
5
0
26
0
30
2
17
0
0
29
12
24
Impact
Factor
3.0
3.0
2.1
2.3
4.3
7.7
7.7
9.7
5.9
5.9
3.4
3.4
3.4
3.4
6.6
2.0
2.8
7.0
29.5
8.0
1.2
3.1
4.6
5.9
2.0
2.0
1.5
10.0
4.8
3.9
7.6
5.6
5.6
10.3
10.3
7.8
3.3
4.5
Gibson, S.B
Gibson, S.B
Gibson, S.B
Gibson, S.B
Gibson, S.B
Gibson, S.B
Hicks, Geoffrey G
Hicks, Geoffrey G
Israels, S.J.
Israels, S.J.
Israels, S.J.
Israels, S.J.
Israels, S.J.
Israels, S.J.
Israels, S.J.
Johnston, J.B.
Johnston, J.B.
Johnston, J.B.
Johnston, J.B.
Johnston, J.B.
Johnston, J.B.
Johnston, J.B.
Johnston, J.B.
Leygue, Etienne
Leygue, Etienne
Leygue, Etienne
Leygue, Etienne
Leygue, Etienne
Leygue, Etienne
Leygue, Etienne
Leygue, Etienne
Leygue, Etienne
Leygue, Etienne
Mai, S.
Mai, S.
Mai, S.
Mai, S.
Mai, S.
Mai, S.
Mai, S.
Mai, S.
Cellular Signalling
Clin Cancer Res.
Int. J. Cancer
J Cell Mol Med.
J. Cell. Sci.
Lymphoma and Leukemia
Cell Cycle
Nucleic Acids Res.
Autophagy
Cell Death Differ.
J Cell Mol Med.
J. Cell. Sci.
J. Thromb. Haemost
Thromb Haemost.
Thromb Haemost.
Am J Hematol
Apoptosis
Blood
Blood
Cellular Signalling
Curr. Med. Chem.
Lymphoma and Leukemia
Transfusion & Apheresis Science
Brit J Cancer.
DNA Cell Biol.
DNA Cell Biol.
Front Biosc.
Front Biosc.
Front Biosc.
Histopathology
Int. J. Cancer
J. Mol. Diagn.
J. Steroid Biochem Mol Biol.
Biopolymers
Cytometry Part A.
Heredity
Int Immunol.
J. Cell. Biochem
J. Cell. Biochem
Nature
Neoplasia
2008
2006
2006
2008
2007
2008
2006
2006
2008
2008
2006
2007
2006
2007
2007
2006
2006
2006
2006
2008
2006
2008
2007
2006
2006
2006
2006
2006
2007
2008
2006
2006
2007
2007
2007
2007
2006
2006
2008
2007
2007
2
13
16
5
25
7
3
38
17
29
25
22
0
2
38
30
0
0
2
38
7
1
12
8
9
1
3
3
1
9
0
4
1
5
1
0
8
0
28
3
4.5
6.0
4.6
4.8
6.6
1.5
3.3
7.0
5.6
7.8
4.8
6.6
5.3
3.2
3.2
1.9
3.9
10.3
10.3
4.5
4.9
1.5
1.2
4.4
2.0
2.0
2.9
2.9
2.9
3.3
4.6
3.1
2.8
2.6
2.4
2.8
6.2
3.4
3.4
29.7
4.7
41
Mai, S.
Mai, S.
Mai, S.
Mai, S.
Mowat, M.R.A.
Mowat, M.R.A.
Mowat, M.R.A.
Murphy, L.C.
Murphy, L.C.
Murphy, L.C.
Murphy, L.C.
Murphy, L.C.
Murphy, L.C.
Murphy, L.C.
Murphy, L.C.
Murphy, L.C.
Murphy, L.C.
Murphy, L.C.
Murphy, L.C.
Murphy, L.C.
Murphy, L.C.
Murphy, L.C.
Shiu, R.P.C.
Shiu, R.P.C.
Shiu, R.P.C.
Watson, P.H.
Watson, P.H.
Watson, P.H.
Watson, P.H.
Watson, P.H.
Watson, P.H.
Watson, P.H.
Watson, P.H.
Watson, P.H.
Watson, P.H.
Watson, P.H.
Watson, P.H.
Watson, P.H.
Watson, P.H.
Watson, P.H.
Watson, P.H.
Watson, P.H.
42
Oncogene
Semin Cancer Biol.
Semin Cancer Biol.
The EMBO J.
Arch. Immunol. Ther. Exp.
J. Cell. Biochem
Mol. Biol. Cell.
Breast Cancer Res Treat.
Breast Cancer Res Treat.
Breast Cancer Res Treat.
Breast Cancer Res Treat.
Brit J Cancer.
Cancer Epidemiology Biomarkers & Prevention
Cancer Res.
Curr. Med. Chem.
Endocr Relat Cancer.
Exp.Cell Res.
Histopathology
J. Biol. Chem.
J. Steroid Biochem Mol Biol.
J. Steroid Biochem Mol Biol.
Mol. Cell. Biochem.
Breast Cancer Res Treat.
DNA Cell Biol.
Front Biosc.
Breast Cancer Res Treat.
Breast Cancer Res Treat.
Breast Cancer Res Treat.
Brit J Cancer.
Cancer Epidemiology Biomarkers & Prevention
Cancer Res.
Cancer Res.
Clin Cancer Res.
DNA Cell Biol.
Endocr Relat Cancer.
Exp.Cell Res.
Histopathology
International Immunology
J. Steroid Biochem Mol Biol.
J. Steroid Biochem Mol Biol.
Psychooncology
Virchows Archiv.
2006
2006
2007
2006
2006
2008
2007
2006
2006
2008
2008
2006
2008
2006
2006
2006
2007
2008
2006
2006
2007
2007
2006
2006
2007
2006
2006
2008
2006
2008
2006
2007
2007
2006
2006
2007
2008
2006
2006
2007
2006
2007
1
0
8
20
10
0
2
2
7
12
1
6
38
1
1
8
7
4
2
2
8
3
2
7
12
1
6
5
1
8
1
1
4
7
4
0
6.6
7.7
7.7
9.5
1.3
3.4
6.7
4.3
4.3
4.3
4.3
4.4
4.5
7.7
4.9
4.9
4.0
3.3
5.9
2.8
2.8
1.7
4.3
2.0
2.9
4.3
4.3
4.3
4.4
4.5
7.7
7.7
6.0
2.0
4.9
4.0
3.3
3.5
2.8
2.8
2.6
2.2
Distribution of Impact Factors in journals of MICB’s published work
2006 - 2008
1%
Impact Factor <5
44%
55%
Impact Factor 5-10
Impact Factor >10
Distribution of Citations of MICB’s published work
2006 - 2008
6%
42%
52%
Citations <5
Citations 5-30
Citations >30
43
Granting Agency
Allen Institute for Brain Science (AIBS)
Amgen Canada Inc
Amira Pharmaceuticals Inc
Bayer Inc.
Canada Research Chair (CRC)
Canadian Breast Cancer Foundation (CBCF)
Canadian Cancer Society (CCS)
Canadian Foundation for Innovation (CFI)
Canadian Institutes of Health Research (CIHR)
CancerCare Manitoba (CCMB)
CancerCare Manitoba Foundation (CCMF)
Carl Zeiss Canada
Diagonstic Services of Manitoba (DMS)
European Commission Research Directorate
Federal Government (FG)
Foundation Fighting Blindness - Canada (FFBC)
Genome Canada (NorCOMM)
Genome Prairie (GP)
GlaxoSmithKline
Health Sciences Center Foundation (HSCF)
Hoffmann La Roche
Hospital for Sick Children (HSC)
Illumina, Inc.
Integrated DNA Technologies
Keystone Symposia
Klick Communications
Leukemia and Lymphoma Society of Canada (LLSC)
Manitoba Health Research Council (MHRC)
Manitoba Institute of Cell Biology (MICB)
Manitoba Institute of Child Health) formally CHF (MICH)
Manitoba Medical College Foundation (MMCF)
Manitoba Medical Services Foundation (MMSF)
Manitoba Research Innovation Fund via WRHA
Mechanisms in Medicine, Inc.
Miscellaneous
National Cancer Institute of Canada (NCIC)
National Research Council (NRC)
Natural Sciences & Engineering Research Council (NSERC)
Provinical Government (PG)
Sigma-Aldrich Canada
Susan G Komen Breast Cancer Foundation (SGKBCF)
The Winnipeg Foundation (TWF)
University of Manitoba (UM)
US Army
TOTAL GRANTS
44
Fellowship/
Operating Equipment Studentship
2
1
1
1
4
10
1
2
33
1
21
1
1
1
3
1
2
7
1
1
3
1
1
1
1
1
4
9
4
1
2
2
1
2
4
6
1
7
1
3
1
14
4
168
Career
6
24
3
5
1
40
1
2
3
4
1
3
4
6
85
7
Total
2
1
1
1
10
10
1
2
57
1
29
1
1
1
4
1
2
7
1
1
3
1
1
1
1
1
4
50
6
4
2
2
1
2
4
10
1
3
12
1
3
1
14
4
266
Inventor
Title
Dr. Arnold Greenberg
• The Nip3 Family of Proteins – Necrosis
Dr. Janice Richman-Eisenstat
• Modulation of Mesenchymal Cells Via IgA-Receptors
Dr. Sabine Mai
• Telomeric Disk
Dr. Sabine Mai
• Methods of Detecting and Monitoring Cancer Using
3D Analysis of Centromeres
Dr. Sabine Mai
• Method of Monitoring Genomic Instability Using
3D Microscopy
Dr. Sabine Mai
• Methods of Diagnosis or Detection Using 3D Analysis
Drs. Mai/Havicauvaa
• Method & System for the 3D Analysis of Chromosomes
Dr. David Eisenstat
• Mutation in the Pro-Apoptotic Protein
BNIP3 as a Biomarker for Solid Tumors
Dr. Geoff Hicks
• A Novel SMART shRNA System for Disease Diagnosis
and Therapy
Dr. Etienne Leygue
• SBEM Promoter
Dr. Marek Los
• Anticancer, Antimicrobial And ImmunoSuppressive Properties Of Brevinin-Like
Peptides
Dr. Marek Los
• Anticancer Peptides Derived From A Viral
Protein Apoptin (VP3)
Dr. Marek Los
• A Novel Role For BAX In The Bystander
Effect
45
Since estrogen is a major driver of human breast cancer, and the action of estrogen changes
during breast tumorigenesis and breast cancer progression, the overall aim of my research
program is to elucidate the mechanisms by which estrogen action changes during the
development of breast cancer and how breast cancers develop resistance to endocrine
therapies and progress from hormone dependence to independence. To do this my group is
identifying the molecular players involved in the estrogen receptor signaling pathways in
human breast tissues, how they are altered during tumorigenesis, and breast cancer
progression to hormone independence. I am specifically determining the types and putative
function of estrogen receptor isoforms, i.e. estrogen receptor alpha and beta and
phosphorylated forms of estrogen receptor alpha, that are expressed in human breast tissues
in vivo, using tissues obtained from the Manitoba Breast Tumor Bank/Clinical Database.
Isoforms that are altered in vivo are tested in laboratory models for the functional
consequences of that alteration. Estrogen signalling may have a role in some lung cancers
so in collaboration with Drs Sri Navaratnam and Gefei Qing, we are developing human
lung cancer tissue microarrays to explore the molecular players involved in the estrogen
signaling pathways in lung tissue. In collaboration with Dr Peter Watson and the Manitoba
Tumorbank, we are also investigating tissue collection issues that may affect detection of
various gene products in banked tissues.
Publications Since 2006
1. George P. Skliris, Brian G. Rowan , Mariam Al-Dhaheri, Christopher Williams, Sandy
Troup, Sanela Begic, Michelle Parisien, Peter H. Watson, Leigh C. Murphy.
Immunohistochemical validation of multiple phospho-specific epitopes for estrogen
receptor a (ERa) in tissue microarrays (TMA) of ERa positive human breast carcinomas.
Breast Cancer Research and Treatment 2008 Dec 23. [Epub ahead of print]
2. Gregory E. Weitsman, Wineeta Weebadda, Kanyarat Ung and Leigh C. Murphy.
Reactive oxygen species induce phosphorylation of serine 118 and 167 on estrogen
receptor alpha. Breast Cancer Research & Treatment 2008 Oct 21. [Epub ahead of
print]
3. Rebecca O. Barnes, Michelle Parisien, Leigh C. Murphy, and Peter H. Watson (2008)
Influence of Evolution in Tumor Biobanking on the Interpretation of Translational
Research. Cancer Epidemiology, Biomarkers & Prevention 17:3344-50.
4. J.M. Flynn, S.D. Dimitrijevich, M. Younes, G. Skliris, L.C. Murphy, and P.R.
Cammarata. 2008 Role of wild-type estrogen receptor-β in mitochondrial cytoprotection
of cultured normal male and female human lens epithelial cells. Am J Physiol
Endocrinol Metab. 295(3):E637-47
46
5. George P. Skliris, Florent Hubé, IonelaGheorghiu, Mark M. Mutawe, Carla Penner,
Peter H. Watson, Leigh C. Murphy, Etienne Leygue, Yvonne Myal. (2008) Expression
of small breast epithelial mucin (SBEM) protein in tissue microarrays (TMAs) of
primary invasive breast cancers. Histopathology 52:355-69
6. Tracy Cherlet and Leigh C. Murphy. (2007) Estrogen Receptors Inhibit Smad3
Transcriptional Activity through Ap-1 Transcription Factors. Mol Cell Biochem
306(1-2):33-4
7. Soma Mandal, Linda Curtis, Molly Pind, Leigh C. Murphy, and Peter H. Watson
(2007) The S100A7, CD74 Connection, Immune Response and Critical Pathways
Promoting Breast Cancer Invasiveness. Exp Cell Res. 313:3016-25
8. George Skliris, Anthony Lewis, Ethan Emberley, Baocheng Peng, Wineeta K.
Weebadda, Angela Kemp, James R. Davie, Robert P. C. Shiu, Peter H. Watson, Leigh
C. Murphy. (2007) Oestrogen receptor-β regulates psoriasin (S100A7) in human
breast cancer. Breast Cancer Res Treat, 104:75-85.
9. Gregory E. Weitsman, Lin Li, George Skliris, James R. Davie, Kanyarat Ung, Yulian
Niu, Linda Curtis-Snell, Ladislav Tomes, Peter H. Watson, Leigh C. Murphy. (2006)
Estrogen receptor-alpha phosphorylated at Serine 118 is present at the promoters of
estrogen-regulated genes and is not altered due to Her2 over-expression. Cancer Res;
66:10162-70.
10.George P. Skliris, Etienne Leygue , Linda Curtis-Snell , Peter H. Watson, Leigh C.
Murphy (2006) Expression of Estrogen Receptor- β in Estrogen Receptor-α Negative
Human Breast Tumours. British J Cancer: 95:616-26.
11. Gregory Weitsman, George Skliris, Kanyarat Ung, Mamoun Younes, Peter H. Watson.
Leigh C. Murphy. (2006) Assessment of Multiple Different Oestrogen Receptor-β
Antibodies for their Ability to Immunoprecipitate under Chromatin
Immunoprecipitation Conditions. Breast Cancer Res Treat, 100(1):23-31.
Chapters and Invited reviews
1.
L.C.Murphy, G.P.Skliris, B. Rowan, M. Al-Dhaheri, C Williams, C. Penner, S.
Troup, S. Begic, Michelle Parisien, P.H.Watson (2009) The Relevance of
Phosphorylated Forms of Estrogen Receptor in Human Breast Cancer in vivo . J
Steroid Biochem Mol Biology in press
2.
George P. Skliris, Etienne Leygue , Peter H. Watson, Leigh C. Murphy. (2008)
Estrogen receptor alpha negative breast cancer patients: estrogen receptor beta as
atherapeutic target. J Steroid Biochem Mol Biology 109 (1-2):1-10. (review)
3.
Leigh Murphy (2007) A Review Of: Estrogen Receptor beta Expression Is
Associated with Tamoxifen Response in ERalpha-Negative Breast Carcinoma
by Gruvberger-Saal, etal., Breast Cancer Online Volume, issue, in press (invited)
4. Leigh C. Murphy, G.E. Weitsman, G.P.Skliris, Evelyn M. Teh, Lin Li, B. Peng, J.R.
Davie, K.Ung, Y-L. Niu, L. Snell, L. Tomes and P.H. Watson and P.H.Watson
) phosphorylated at serine 118
(2006) Potential role of estrogen receptor (
in human breast cancer in vivo. J Steroid Biochem Mol Biology 102 (1-5): 13946 (invited presentation)
5. Suresh Mishra, Leigh C Murphy and Liam J. Murphy (2006) The Prohibitins:
Emerging roles in diverse functions. Journal of Cellular and Molecular Medicine
10(2):353-63 (invited review)
47
6. George Skliris, Leigh Murphy. (2006) A Review On: Methylation of estrogen
receptor promoter correlates with loss of ER- expression in mammary carcinoma and
is an early indication marker in premalignant lesions. Breast Cancer Online Volume
9, issue 9, September 2006. (invited)
7. James B. Johnston, Sri Navaratnam, Marshall W. Pitz, J. Maniate, Emilia Wiechec,
Heinrich Baust, J. Gingerich, Georgios P. Skliris, Leigh C. Murphy and Marek
Los. (2006) Targeting the EGFR pathway for cancer therapy. Current Medical
Chemistry13(29):3483-92
8. Leigh C. Murphy and Peter H Watson. (2006) Is Oestrogen Receptor- Predictor of
Endocrine Therapy Responsiveness in Human Breast Cancer?
Endocrine Related Cancer . 13: 327-334.
Invited Seminars and Presentations at Symposia/Meetings
1. March 17, 2009 – Estrogen receptor profiling in human breast cancer towards better
prediction of endocrine therapy response. Monash Institute of Medical Research,
Melbourne, Australia.
2. November 5, 2008 - The multifaceted nature of estrogen signaling in breast cancer,
Nova Scotia Cancer Research Symposium. Halifax, Nova Scotia
3. November 6, 2008- Estrogen Receptor Profiling in Human Breast Cancer: towards the
better prediction of endocrine therapy response. Dept of Biochemistry and Molecular
Biology, Dalhousie University, Halifax, Nova Scotia
4. September, 2008. Potential role of phosphorylated estrogen receptors in human breast
cancer in vivo. 18th International Symposium of the Journal of Steroid Biochemistry
& Molecular biology – Recent Advances in Steroid Biochemistry & Molecular
biology. Seefeld, Tyrol, Austria. 18-23 Sept, 2008.
5. August 12-16th 2008 4thPacRim Conference on Breast and Prostate Cancer, Whistler,
BC. Estrogen Receptor Profiling in Human Breast Cancer.
6. June 2008. Estrogen receptor profiling in human breast cancer - towards better
prediction of endocrine therapy response. CancerCare Manitoba Breast Cancer
symposium. Associated with the WBCC, Winnipeg, June 6th, 2008
7. June 2008. Estrogen receptor profiling in human breast cancer - towards better
prediction of endocrine therapy response. Breast Cancer Research Forum - BCCA,
Vancouver, June 17-18.
8. February 13, 2008. Cancer 101: Cellular and molecular basis of cancer. Presentation
to high school students, Hastings School, Winnipeg - contact Teresa Baril-Bissette.
9. June 2007. The Manitoba Tumour bank presentation to the Thoracic Disease Site
Group Rounds/CancerCare Manitoba.
10. May 2006. Potential role of estrogen receptor alpha phosphorylated at serine 118 in
human breast cancer in vivo. 17th International Symposium of the Journal of Steroid
Biochemistry & Molecular biology - Recent advances in steroid biochemistry &
molecular biology. Seefeld, Tyrol, Austria. 31 May- 3 June 2006. Unable to attend
due to serious family illness.
11. May, 2006. Tumorbanking and Breast Cancer Research. Biobanking in Manitoba
Workshop. Fort Garry Hotel, Winnipeg.
Special Awards and Distinctions
Member of the Canada Foundation for Innovation, 2007 to present
Administrative Service - MICB
Director (Acting ) January 2009 to present
Associate Director, April 1, 2006 to Dec 2008
Member, Executive Committee MICB - 2000 to present
Member, Space Committee - 2000 to present
Member, Manitoba Breast Tumor Bank Scientific Review Panel – 2003 to present
Department
Department of Biochemistry and Medical Genetics
Academic Standards – member
Graduate Students Acceptance Committee - Chair 2000 to 2008
Member, Medicine Teaching Committee - 2000 to present
Member, Candidacy examination committee - 2000 to present
Faculty and University Level
Member, Search Committee Head of Pharmacology, Faculty of Medicine
Member, selection committee for the Head of Human Genetics, Faculty of Medicine.
Member of the Accreditation Committee Considering the Faculty, U of Manitoba.
Biochemistry Representative on the Reproductive Systems Committee for Medical
Student Curriculum Reform, U of Manitoba.
Chair for PhD Oral Defense of Sandra Koesters, Dept of Medical Microbiology,
University of Manitoba, February, 2007
Chair for PhD Oral Defense of Harjot Chohan, Dept of Physiology, University
of Manitoba. July, 2007
Member of review panel for Winnipeg Rh Award nominees 2005-08
Professional Service
Scientific Reviewer, DOD-BCRP-Concept Grants- Endocrinology panel, February, 2008
Scientific Reviewer, CIHR- Endocrinology Panel. November 2008
Chair- Fellowship Review Panel MHRC. 2008, 2009
Scientific Reviewer USAMRMC - Breast Cancer Research Initiative, Endocrinology
panel 2, 2008
Scientific Reviewer Personnel Awards panel MHRC - 2007
Member of the College of Reviewers for the Canada Research Chairs Program: 2000 to
present
Alberta Cancer Board - Breast Cancer Research Program- scientific reviewer January,
2006, 2008, 2009
Community Service
Member, UICC International Fellowships Review Panel (ICRETT Panel, disciplines
biochemistry. Molecular biology, biophysics) 1999 to present
Member of the Clinical Endocrinology Subcommittee of the Clinical Research Section
of the 2006 AACR Program Committee.
Keynote Speaker at Guardian Angels Youth Cancer Awareness Program, October, 2006
49
Epigenetic is a term used to describe changes in gene expression that are stable between
cell divisions. Chromatin modifying enzymes including lysine acetytransferases
(KATs), histone deacetylases (HDACs), histone kinases, histone phosphatases,
lysine/arginine methyltransferases, lysine/arginine demethylases, ATP-dependent
chromatin remodeling complexes and DNA methyltransferases mediate chromatin
remodeling and are components of a complex epigenetic network regulating gene
expression during development, differentiation and disease. Multistep tumorigenesis is a
progression of events resulting from alterations in the processing of the genetic
information. These alterations result from stable genetic changes (mutations) in tumor
suppressor genes and oncogenes (e.g. ras) and potentially reversible epigenetic changes.
DNA methylation and histone post-translational modifications (PTMs) are two
epigenetic mechanisms that are altered in cancer cells.
The mammalian cell’s nucleus is highly organized, with transcription factors and
factories, chromatin modifying enzymes, and chromosomes having defined sites.
Altered nuclear structure and function (gene expression) underlie the development and
progression of cancer.
Dr. Davie’s research program has three research themes designed to understand the roles
of chromatin dynamics and nuclear structure in gene expression in normal and cancer
cells: i) to characterize histone PTMs and chromatin modifying enzymes associated
with transcribed chromatin; ii) to investigate the mechanisms by which signal
transduction pathways control chromatin dynamics; iii) to explore the role of the
nuclear matrix in chromatin dynamics and to identify nuclear matrix proteins
informative in cancer diagnosis.
Publications Since 2006
1.
Delcuve, G.P., Espino, P.S. and Davie, J.R. (2009) Role of H3 phosphorylation in
different biological processes in normal and disease states. In: Epigenetics:
Mechanisms, Functions, and Effects in Humans; Nova Science Publishers, Inc.
In press
2.
Espino, P.S., Pritchard, S., Heng, H.H.Q. and Davie, J.R. (2009) Induction of H3
phosphorylation at serine 10 by the Ras-MAPK pathway in pancreatic cancer
cells. Int. J. Cancer. 124, 562-7.
50
.
.
.
.
.
.
.
Dunn, K.L., He, S., Wark, L., Mai, S., Delcuve, G.P., Sun, J.M., Chen, H.Y. and
Davie, J.R. (2009) Increased genomic instability and altered chromosomal protein
phosphorylation timing in Ha-ras-transformed mouse fibroblasts. Genes,
Chromosomes and Cancer. 48, 397-409.
Delcuve, G.P., Rastegar, M. and Davie, J.R. (2009) Epigenetic control. J. Cell.
Physiol. 219, 243-250.
Pérez-Cadahía, B., Drobic, B. and Davie, J.R. (2009) H3 phosphorylation: dual role
in mitosis and interphase. Biochem. Cell. Biol. In press.
Healy, S., Pérez-Cadahía, B., Jia, D., McDonald, M.K., Davie, J.R. and Gravel, R.
(2009) Biotin is not a natural histone modification. Biochim. Biophys. Acta (Gene
Regulatory Mechanisms) In review.
Kien, C.L., Peltier, C.P., Mandal, S., Davie, J.R. and Blauwiekel, R. (2008) Effects
of the in vivo supply of butyrate on histone acetylation of cecum in piglets. J.
Parenter. Enteral Nutr. 32, 51-6.
He, S., Dunn, K.L., Espino, P.S., Drobic, B., Li, L., Yu, J., Sun, J.M., Chen, H.Y.,
Pritchard, S. and Davie, J.R. (2008) Chromatin organization and nuclear
microenvironments in cancer cells. J. Cell. Biochem. 104, 2004-15.
Delcuve, G.P., He, S. and Davie,J.R. (2008) Mitotic partitioning of transcription
factors. J. Cell. Biochem. 105, 1-8.
Li, L. and Davie, J.R. (2008) Association of Sp3 and estrogen receptor alpha with
the transcriptionally active trefoil factor 1 promoter in MCF-7 breast cancer cells. J.
Cell. Biochem. 105, 365-9.
Stein,G.S., Davie, J.R., Lnowlton, J.R. and Zaidi, S.K. (2008) Nuclear
microenvironments and cancer. J. Cell. Biochem. 104, 1649-52.
Davie, J.R., He, S, Li, L., Sekhavat, A., Espino, P., Drobic, B., Dunn, K.L., Sun,
J.M., Chen, H.Y., Yu, J., Pritchard, S. and Wang, X. (2008) Nuclear organization and
chromatin dynamics – Sp1, Sp3 and histone deacetylases. Adv Enzyme Regul. 48,
189-208.
Zhang, X., Soong, R., Wang, K., Li, L., Davie, J.R., Guarcello, V. and Diasio, R.B.
(2007) Suppression of DPYD expression in RKO cells via DNA methylation in the
regulatory region of DPYD promoter; a potentially important epigenetic mechanism
regulating DPYD expression. Biochem. Cell. Biol. 85, 337-346.
Sun, J.-M., Chen, H.Y. and Davie, J.R. (2007) Differential distribution of
unmodified and phosphorylated histone deacetylase 2 in chromatin. J.Biol. Chem.
282, 33227-36.
Mandal, S. and Davie, J.R. (2007) An integrated analysis of genes and pathways
exhibiting metabolic differences between estrogen receptor positive breast cancer
cells. BMC Cancer. 7, 181.
Sekhavat, A., Sun, J.M. and Davie, J.R. (2007) Competitive inhibition of histone
deacetylase activity by trichostatin A and butyrate. Biochem. Cell. Biol., 85, 751758.
51
. Sun, J.-M., Chen, H.Y., Espino, P.S. and Davie, J.R. (2007) Phosphorylated serine 28
of histone H3 is associated with destabilized nucleosomes in transcribed chromatin.
Nucleic Acids Res., 35, 6640-7.
. Drobic, B., Dunn, K.L., Espino, P.S. and Davie, J.R. (2006) Abnormalities of
chromatin in tumour cells. In: Cancer: Cell Structures, Carcinogens and Tumor
Pathogenesis; EXS; Birkhäuser Verlag’; edited by Leon Bignold. 96, 25-47.
(CSBMCB) Meeting on Chromatin Structure and Function, Banff, March 5-9, 2008
-21,
2007 at Saxtons River, Vermont
-Organizer, FASEB Summer Conference on "Nuclear Structure and Cancer", June 14-19,
2009 at Saxtons River, Vermont
-Chair, US National Cancer Institute think tank on nuclear structure and cancer,
Feb 2006
-19, 2009 at
Saxtons River, Vermont
Meeting of the Canadian Oxidative Stress Consortium, May 7-10, 2009 at Winnipeg,
Manitoba
International Conference on Functional Annotation of the Mammalian Genome, April
25-27, 2009 at Banff, Alberta
Code” November 9-10, 2007 at Barcelona, Spain
-20, 2007 at University of New England,
Biddeford, ME
-21, 2007 at
Saxtons River, Vermont
Histone Deacetylases”, June 2-7, 2007 at Snowmass
Village, Colarado
Neoplastic Tissues”, September 24-25, 2007, University of Bologna, Italy
-10, 2007 at School of Biological
Sciences, University of Concepción, Concepción, Chile
2006 (co-organizer)
Schulich School of Medicine & Dentistry, University of
Western Ontario, London, November 2008
Laramie, Wyoming, October 2008
University of Manitoba Continuing Medical Education, Winnipeg, Sept 2007
University of Montreal. Montreal, Quebec, February 2006
2009
-
Foundation of Canada, June 2008
Cancer Institute, Washington DC, June 4-5, 2008
pre-doctoral traineeship award in breast cancer, March 2008
NorCOMM Scientific Advisory Board (Genome Canada), 2005-present
Sciences, 2008
and Microbiology at the University of Victoria, March 19-20, 2008
Centre for Life Course
Health, 2007
53
Member of the Editorial Board
Editor, Biochemistry and Cellular Biology, 1999 - present
Journal of Biological Chemistry (1997-2002, 2006-2011)
Clinical Epigenetics (current)
Journal of Cellular Biochemistry (current)
International Journal of Cell Biology (current)
International Journal of Biochemistry and Cell Biology
Molecular Biology Reports (current)
Gene Therapy and Molecular Biology
Critical Reviews in Eukaryotic Gene Expression (2005-08)
The research conducted in my laboratory is directed toward understanding the
regulation of cell growth and differentiation during development. These investigations
are of primary importance to childhood cancers. In Manitoba, cancer is the most
common cause of death in childhood and adolescence, excluding accidents. Current
treatment strategies, which primarily involve radiation and chemotherapy, do not
directly target the cancer cell. In contrast, biological response modifiers have been
used to treat several types of malignancy by harnessing normal developmental
programs specific to these relatively undifferentiated cancer cell populations. The
primary aim of my research program is to facilitate our understanding of the processes
of differentiation of cells through changes in their internal milieu and external
environment. I propose to accomplish this through an improved understanding of two
important regulatory molecules: (i) the hypoxia-inducible cell death protein, BNIP3 (in
collaboration with Dr. Spencer Gibson) in brain tumours of children and adults; and (ii)
the DLX homeodomain proteins that are transcription factors in the developing brain,
retina, pancreas and intestine. The ultimate goal is to develop novel therapeutic
approaches complementing current treatment strategies by modifying neuronal
differentiation programs in paediatric malignancies, including neuroblastoma,
retinoblastoma and brain tumours.
Publications Since 2006
1. Eisenstat DD, Gibson SB. (2009) RIGging functional outcomes in glioma cells: new
insights into LRIG proteins in glioma cells. Cancer Biol. Ther. 8, 1024-6.
2. Johnston DL, Keene D, Bartels U, Carret AS, Crooks B, Eisenstat DD, Fryer C,
Lafay-Cousin L, Larouche V, Moghrabi A, Wilson B, Zelcer S, Silva M, Brossard J,
Bouffet E. (2009) Medulloblastoma in children under the age of three years: a
retrospective Canadian review. J. Neuro-oncol. 94, 51-56.
3. Burton T, Eisenstat DD, Gibson SB. (2009) Bcl-2 Nineteen kilodalton Interacting
Protein (BNIP3) acts as a transcriptional repressor of Apoptosis Inducing Factor
(AIF) expression preventing cell death in human malignant gliomas. J. Neurosci.
29, 4189-4199.
4. Eisenstat DD. (2008) Chromatin immunoprecipitation. In: Binder MD, Hirokawa N,
Windhorst U, Hirsch MC (Eds.) Encyclopedia of Neuroscience, 4th Edition,
Springer: Heidelberg.
5. Miao P, Madec K, Gong Y, Shen H, Eisenstat D, Melanson M, Gu X, Leong C,
Klowak M, Namaka M. (2008) Axotomy-induced upregulation of Tumor Necrosis
Factor-Alpha in the dorsal root ganglia. Neurol. Res. 30, 623-631.
55
6. Wigle JT, Eisenstat DD. (2008) Homeobox genes in vertebrate forebrain
development and disease. Clin. Genet. 73, 212-226.
7. de Melo J, Zhou QP, Wigle JT, Eisenstat DD. (2008) Dlx2 homeobox gene
transcriptional regulation of the TrkB neurotrophin receptor expression during
mouse retinal development. Nucleic Acids Res. 36, 872-884.
8. Koul R, Dufan T, Dubey A, Schroeder G, Jones K, Vijay K, Eisenstat DD. (2008)
Imaging features of primary central nervous system lymphoma at presentation. Case
series from a regional cancer centre. Oncology Exchange 7, 24-27.
9. Johnston DL, Keene DL, Lafay-Cousin L, Steinbok P, Carret AS, Crooks B,
Strother D, Wilson B, Odame I, Eisenstat DD, Mpofu C, Zelcer S, Huang A,
Bouffet E. (2008) Supratentorial Primitive Neuroectodermal Tumors: A Canadian
Pediatric Brain Tumor Consortium Report. J. Neuro-Oncol. 86, 101-8.
10. Wigle JT, Eisenstat DD. (2008) Common signaling pathways used during
development. Ch. 21. In: Moore KL, Persaud TVN, The Developing Human, 8th
Edition, Elsevier Science: Saunders, Philadelphia.
11. Kvakovski A, Schvirtlich M, Zhang Q, Eisenstat DD, Erdélyi F, Baranyi M,
Katarova ZD, Szabó G. (2007) GAD and Dlx isoforms exhibit distinct
spatiotemporal expression patterns in the developing mouse lens. Dev. Dyn. 236,
3532-3544.
12. Le TN, Du G, Fonseca M, Zhou QP, Wigle JT, Eisenstat DD. (2007) Dlx homeobox
genes promote cortical interneuron migration from the basal forebrain by direct
repression of the semaphorin receptor neuropilin-2. J. Biol. Chem. 282, 1907119081.
13. Lamparello P, Baybis M, Pollard J, Hol EM, Eisenstat DD, Aronica E, Crino PB.
(2007) Developmental lineage of cell types in cortical dysplasia with balloon cells.
Brain 130, 2267-2276.
14. Mason WP, Del Maestro R, Eisenstat D, Forsyth P, Fulton D, Laperrière N,
Macdonald D, Perry J and Thiessen B. (2007) Canadian recommendations for the
treatment of glioblastoma multiforme. Curr. Oncol. 14, 110-117.
15. Keene DL, Johnston DL, Strother D, Brossard J, Carret A, Crooks B, Eisenstat D,
Fryer C, Mpofu C, Moghrabi A, Odame I, Zelcer S, Silva M, Wilson B, Samson Y,
Hand J, Bouffet E. (2007) Epidemiological survey of central nervous system germ
cell tumors in Canadian children. J. Neuro-Oncol. 82, 289-295.
16. Salman M, Froese N, Shuckett P, Wrogemann J, Eisenstat DD. (2006) Claude
Syndrome “plus” in an adolescent. Can. J. Neurol. Sci. 33, 430-432.
17. Ghashghaei HT, Weber J, Pevny L, Schwab M, Lloyd KCK, Eisenstat DD, Lai C,
Anton ES. (2006) The role of neuregulin-ErbB4 interactions on the proliferation
and organization of cells in the subventricular zone. Proc. Natl. Acad. Sci. USA
103, 1930-1935.
18. Burton TR, Henson ES, Baijal P, Eisenstat DD, Gibson SB. (2006) The pro-cell
death Bcl-2 family member, BNIP3, is localized to the nucleus of human glial cells:
implications for glioblastoma multiforme tumor cell survival under hypoxia. Int. J.
Cancer 118, 1660-1669.
Abstracts and Conference Presentations since 2006
1. Zhang Q, Cheng SH, Eisenstat D.(2009) Dlx transcription factors regulate the
Brn3b homeobox gene during vertebrate retina development. Developmental
Biology 331, 431. [poster]
2. Eisenstat DD, Tan Y, Zhang S. (2009) Boundary dispute in the developing
forebrain – DLX2 vs. PAX6. Developmental Biology 331, 524. [poster]
3. Nafez S, Oikawa K, Odero G, Ge N, Zhang D, Abrenica B, Czubryt M, Eisenstat
D, Albensi BC. (2009) Early Growth Response 2 (EGR2) is induced by neuronal
activity-dependent NF-KB activation. Basic & Clinical Pharmacology &
Toxicology 105 (Suppl. 1), 116-117. [poster]
4. Carter T, Fonseca M, Lum-Min SA, Hancock BJ, Eisenstat DD and Grynspan D.
(2009) Absence of evidence of apoptosis or ganglion cell damage at the
transformation zone in Hirschsprung’s Disease. Canadian Association of
Pathologists 60th Annual Meeting. [poster]
5. Le T, Zhang S, Eisenstat D. (2008) Genetic regulation of CNS stem cell
differentiation and migration – role of DLX homeobox genes. Neuro-Oncol 10,
906.[poster]
6. Zhang Q, Eisenstat DD. (2008) DLX transcription factors regulate the Brn3b
homeobox gene during vertebrate retinal development. 3rd Alberta Vision
Sciences Symposium. [platform]
7. Lafay-Cousin L, Keene D, Carret AS, Crooks B, Eisenstat D, Fryer C, Johnston
D, Larouche V, Moghrabi A, Wilson B, Whitton A, Zelcer S, Bouffet E. (2008)
CNS atypical teratoid rhabdoid tumor (ATRT) in children less than 36 months: A
Canadian pediatric brain tumor consortium experience. Neuro-Oncol. 10, 370.
8. Le T, Pind M, Eisenstat D. (2008) Genetic regulation of CNS stem cell
differentiation and migration: Role of DLX homeobox genes. Neuro-Oncol. 10,
382-3. [platform]
9. Stempak D, Gammon J, Stephens D, Feltis A, Bartels U, Fryer C, Hukin J,
Eisenstat D, Johnston D, Samson Y, Bouffet E, Baruchel S. (2008) A Canadian
multicenter pilot study of extended low dose temozolomide and radiation therapy
in pediatric brainstem glioma. Neuro-Oncol. 10, 391. [platform]
10. Crooks B, Keene D, Carret AS, Bartels U, Eisenstat D, Fryer C, Lafay-Cousin L,
Larouche V, Moghrabi A, Silva M, Zelcer S, Bouffet E. (2008) Brainstem tumors
in infants < 3 years old in Canada 1990-2005: Report of the Canadian Pediatric
Brain Tumor Consortium. Neuro-Oncol. 10, 411. [poster]
11. Zelcer S, Keene D, Carret AS, Crooks B, Eisenstat D, Johnston D, Fryer C,
Lafay-Cousin L, Larouche V, Moghrabi A, Wilson B, Whitton A, Bouffet E.
(2008) Spinal cord tumors in infancy: A Canadian pediatric brain tumor
consortium report. Neuro-Oncol. 10, 416. [poster]
12. Keene D, Lafay-Cousin L, Carret AS, Crooks B, Eisenstat D, Fryer C, Johnston
D, Larouche V, Moghrabi A, Silva M, Wilson B, Zelcer S, Bouffet E. (2008) The
Canadian Pediatric Brain Tumor Consortium national survey of CNS tumors in
children under 3 years of age. Neuro-Oncol. 10, 416. [platform]
13. Johnston D, Keene D, Bartels U, Carret AS, Crooks B, Eisenstat D, Fryer C,
Lafay-Cousin L, Larouche V, Moghrabi A, Wilson B, Zelcer S, Bouffet E. (2008)
Medulloblastoma in children under 3 years of age: A retrospective Canadian
review. Neuro-Oncol. 10, 435. [poster]
57
14. Burton TR, Eisenstat DD, Gibson SB. (2008) Bcl-2 Nineteen kilodalton
Interacting Protein (BNIP3) promotes tumour cell survival in Glioblastoma
Multiforme (GBM) by transcriptionally silencing pro-cell death gene expression.
13th Biannual Can. Neuro-Oncol. Conf. (Calgary AB) [platform].
15. Carret AS, Keene D, Bartels U, Crooks B, Eisenstat D, Fryer C, Lafay-Cousin L,
Larouche V, Moghrabi A, Silva M, Wilson B, Zelcer S, Bouffet E. (2008)
Epidemiological survey of histologically confirmed low-grade gliomas in
children < 36 months of age: A Canadian pediatric brain tumour consortium
(CPBTC) study. Neuro-Oncol. 10, 447. [poster]
16. Le TN, Zhou QP, Vriend J, Eisenstat DD. (2008) GABAergic interneuron
differentiation in the basal forebrain is mediated by direct regulation of glutamic
acid decarboxylase isoforms by Dlx homeobox genes. 4th Can. Dev. Biol. Conf.
(Banff AB) [poster].
17. de Melo J, Zhou QP, Zhang Q, Zhang S, Fonseca M, Wigle JT, Eisenstat DD.
(2008) DLX2 homebox gene directly regulates TrkB neurotrophin receptor
expression during mouse retinal development. 4th Can. Dev. Biol. Conf. (Banff
AB) [poster].
18. Burton TR, Eisenstat DD, Gibson SB. (2008) Bcl-2 Nineteen kilodalton Eshraghi
M, Jangamreddy JR, Herbert K, Eisenstat DD, Wigle JT. (2008) Transcriptional
activation of lymphatic endothelial growth factors by the PROX1 homeodomain
protein. 4th Can. Dev. Biol. Conf. (Banff AB) [poster].
19. Lou H, Eisenstat D, Parry D. (2008) Whole Blood Analysis is an Effective Way
to Avoid Pseudohyperkalemia in Patients with Acute Lymphocytic Leukemia.
Clin. Biochem. 41, 185-186. [poster]
20. Dueck CC, Eisenstat DD, Grynspan D, Caces R, Rafay MF. (2008) Perinatal
stroke secondary to chorioamnionitis: a histopathological case presentation. 43rd
Canadian Neurological Sciences Federation Meeting (Victoria BC) [poster]
21. Zhang Q, Du G, Ekker M, Eisenstat DD. (2007) Transcriptional control by Dlx
homeobox genes of evolutionarily conserved regulatory elements during
vertebrate retinal development. Soc. Neurosci. 37th Ann. Meeting (San Diego)
[poster].
22. Tan Y, Kuzenko N, Eisenstat DD. (2007) Boundary dispute in the developing
vertebrate forebrain: Pax6 versus Dlx2. Soc. Neurosci. 37th Ann. Meeting (San
Diego) [poster].
23. Bouffet E, Carret AS, Crooks B, Hukin J, Eisenstat D, Wilson B, Odame I, Zelcer
S, Johnston D, Silva M, Mpofu C, Samson Y, Brossart J, Moghrabi A, Strother D.
(2007) The Canadian paediatric brain tumour consortium (CPBTC): A model of
cooperation using teleconferencing services. Neuro-Oncol. 9, 221.
24. Mechtler L, Alksne J, Wong E, Arenson E, Recht L, Avgeropolous N, Eisenstat
D, Hormigo A, Perry J, Raizer J, Shapiro W, Taylor L, Shulman M, Carr L.
(2006) Interim Report of the Phase III open-label study of XERECEPT
(corticorelin acetate injection) for treatment of peritumoral brain edema in
patients with primary or secondary brain tumors. Neuro-Oncol. 8, 446-447.
[poster].
25.
26.
27.
28.
29.
30.
31.
Zhang S, Perry A, Xue F, Henson E, Gibson SB, Eisenstat DD. (2006) The hypoxia
inducible BCL-2 homologue BNIP3 is mutated in oligodendroglial tumours.
Neuro-Oncol. 8, 404-405 [platform].
Bristow NA, Henson ES, Vegh-Yarema N, Eisenstat DD, Gibson SB. (2006) The
pro-cell death Bcl-2 family member, BNIP3, is mutated in breast tumors and this
mutation increases resistance to hypoxia-induced cell death in breast cancer cell
lines. Proc. Amer. Assoc. Cancer Res. 97th Ann. Meeting (Washington) [poster].
Webb MB, Henson ES, Chen Y, McMillan-Ward EM, Israels SJ, Eisenstat DD,
Gibson SB. (2006) Hypoxia inducess beclin-1 expression and autophagic cell death
in apoptosis-competent cells. Proc. Amer. Assoc. Cancer Res. 97th Ann.
Meeting (Washington) [poster].
Tran MN, Ronald S, West M, Eisenstat DD, Ryner LN. (2006) Spectroscopic
imaging of gamma-knife targeted neoplasms. 12th Biannual Can. Neuro-Oncol.
Conf. (Winnipeg MB) [platform].
Zhang S, Xue F, Perry A, Gibson SB, Eisenstat DD. (2006) The Bcl-2 homolog
BNIP3 is mutated in oligodendroglial tumours. 12th Biannual Can. Neuro-Oncol.
Conf. (Winnipeg MB) [poster].
Burton TR, Eisenstat DD, Gibson SB. (2006) Glioblastoma multiforme tumors can
survive in hypoxic conditions by localizing BNIP3 to the nucleus. 12th Biannual
Can. Neuro-Oncol. Conf. (Winnipeg MB) [poster].
Bouffet E, Carret AS, Crooks B, Hukin J, Eisenstat D, Wilson B, Odame I, Zelcer
S, Johnston D, Silva M, Mpofu C, Samson Y, Brossart J, Moghrabi A, Strother D.
(2006) The Canadian Paediatric Brain Tumour consortium (CPBTC): a model of
cooperation using teleconferencing services. 12th Biannual Can. Neuro-Oncol.
Conf. (Winnipeg MB) [platform].
32. Johnston D, Keene D, Lafay-Cousin L, Steinbok P, Carret AS, Crooks B, Strother
D, Wilson B, Odame I, Eisenstat D, Mpofu C, Zelcer S, Huang A, Bouffet E.
(2006) Treatment and outcome of supratentorial primitive neuroectodermal
tumours: a report from the Canadian Pediatric Brain Tumour Consortium. 12th
Biannual Can. Neuro-Oncol. Conf. (Winnipeg MB) [platform].
33. Keene D, Johnston D, Bouffet E, Brossard J, Carret AS, Crooks B, Eisenstat D,
Fryer C, Mpofu C, Moghrabi A, Odame I, Strother D, Zelcer S, Silva R, Wilson
B. (2006) National Epidemiological Survey of Pediatric CNS Germ Cell Tumor
Occurrence in Canada. 12th Biannual Can. Neuro-Oncol. Conf. (Winnipeg
MB) [poster].
Invited Seminars and Presentations at Symposia/Meetings
1. Health Canada, Ottawa, Ontario. “Therapy in Malignant Gliomas: Targeting the
Epidermal Growth Factor Receptor”, February 25, 2009.
2. Brain Tumour Foundation of Canada, London, Ontario. “Medulloblastoma in
Children and Adults: Advances in Biology and Treatment”. Patient Information
Day, Oct. 18, 2008.
3. London Health Sciences Centre, London, Ontario. “Medulloblastoma in Children
and Adults: Clinical management and prognostic factors”, Oct. 17, 2008.
59
4. Collaborative Graduate Program in Developmental Biology, University of Western
Ontario, London, Ontario. “Transcriptional regulation of forebrain development and
relevance to neurodevelopmental disorders”, Oct. 17, 2008.
5. Visiting Professors in Medical Education Series, Faculty of Medicine, University of
Calgary, Calgary, Alberta. “The Advanced Degrees in Medicine Program at the
University of Manitoba”, September 17, 2008.
6. Genes and Development Research Group Seminar, Faculty of Medicine, University
of Calgary, Calgary, Alberta. “Regulation of brain development and
neurodevelopmental disorders by homeobox genes.” September 17, 2008.
7. University of Colorado Cancer Center Symposium Series, Denver, Colorado
“Transcriptional regulation of forebrain development: implications for
neurodevelopmental disorders and CNS tumors, April 14, 2008.
8. Texas Children’s Cancer Center Rounds, Texas Children’s Hospital, Houston, Texas
“Regulation of forebrain development by DLX homeobox genes – implications for
neurodevelopmental disorders and tumors”, Feb. 8, 2008.
9. Neuroscience Research Colloquium, Brain Research Centre, University of British
Columbia, Vancouver BC “ChIPping away at the brain – transcriptional regulation
of forebrain development by DLX homeobox genes”, Jan. 18, 2008
10. Children’s Mercy Hospital and Department of Pediatrics, University of Missouri,
Kansas City School of Medicine “DLX homeobox genes in forebrain development
and relevance to autism”, Dec. 4, 2007.
11. Bowman Neonatal Research Symposium, Department of Pediatrics, University of
Manitoba. “What can mouse models teach us about the developing brain?”, Sept.
20, 2007.
12. Distinguished Lecturer Series. Hospital for Sick Children, University of Toronto
“ChIPping away at the brain – transcriptional regulation of forebrain development
by DLX homeobox genes”, Feb. 15, 2007.
13. Neurosciences Grand Rounds, Vancouver General Hospital, University of British
Columbia, Vancouver BC “DLX homeobox genes in forebrain development –
relevance to GABAergic neuronal differentiation and migration”, Sept. 27, 2006.
14. British Columbia Children’s Hospital, University of British Columbia, Vancouver
BC “Hypoxia, cell death genes and brain tumours – role of the BCL2 homolog
BNIP3”, Sept. 26, 2006.
15. Canadian Congress of Neurological Sciences Education Day, Montreal, Quebec
Course leader: “Advances in Neuro-Oncology: Primary Central Nervous System
Lymphoma”, June 14, 2006.
16. Schering Canada Advisory Board, 12th Biennual Canadian Neuro-Oncology
Meeting, Winnipeg, Manitoba “Glioblastoma multiforme algorithm: duration of
therapy”, May 26, 2006.
17. Vision in the Prairies Symposium, University of Winnipeg “Genetic regulation of
retinal ganglion cell differentiation and survival”, April 27, 2006.
Professional Service
Grant review committees
1. Leukemia and Lymphoma Society of Canada, panel member, 2009-present
2. National Brain Tumor Society (USA), Scientific Advisory Committee and panel
member, 2009-present.
3. Austrian Science Foundation, external reviewer, 2008-present.
4. Brain Tumor Society (USA), Low Grade Gliomas, panel member, 2007-2008.
5. C17 Research Network, Canadian Pediatric Hematology-Oncology Program
Directors, external reviewer, 2007-present.
6. National Cancer Institute of Canada (NCIC), Clinical Research Fellowship, panel
member, 2006-present.
7. Canadian Foundation for Innovation (CFI), external reviewer, 2006-present.
8. Brain Tumor Funders’ Collaborative, Scientific Advisory Committee and panel
member, 2005-present.
9. CIHR, external reviewer, 2004-present.
10. Canadian Diabetes Association, external reviewer, 2004-present.
11. Natural Sciences and Engineering Research Council (NSERC), external reviewer,
2003-present.
12. Samantha Dickson Charitable trust (UK), external reviewer, 2003-present.
13. Alberta Cancer Board, external reviewer, 2003-present
14. Ontario Cancer Research Network (OCRN)/Ontario Institute of Cancer Research
(OICR), panel member, clinical & translational operating grants committee, 20022008.
Journal Reviewer
Acta Neuropathologica
Acta Paediatrica
Brain Research
Cancer Research
Clinical Cancer Research
Development
Developmental Dynamics
Journal of Engineering in Medicine
Molecular Brain Research
Neuroscience
61
Discovering Signal Transduction Pathways Regulating Cell Death
In maintaining integrity and homeostasis of multicellular organisms, the balance between
cell death and survival is fundamentally important. When this balance is altered diseases
occur such as cancer. One protein important in regulation of cell death is the Bcl-2 BH-3
only member BNIP3. BNIP3 expression is induced under low oxygen (hypoxia)
conditions and is over expressed in solid tumors in hypoxic regions. When BNIP3 is over
expressed in cancer cells it induces cell death mediated by mitochondrial dysfunction.
This cell death instead of being apoptotic is autophagic (a new form of programmed cell
death). This paradox of BNIP3 killing cancer cells and being over expressed in live cells
within tumors is a focus of our research. To date three explanations could account of
these differences. The first difference is growth factors block BNIP3 cell death function
and tumors have deregulated growth factor signaling leading to cell survival (see below).
Secondly, BNIP3 is also localized in the nucleus of tumor cells prevent its interaction
with the mitochondria blocking its cell death function. Finally, the BNIP3 gene is
mutated to an inactive protein. This protein acts in a dominant negative fashion blocking
hypoxia induced cell death. The importance of these mechanisms for cancer progression
and treatment is under active investigation.
Cell survival is as important as cell death. The epidermal growth factor receptor (EGFR)
is expressed at high levels in several cancers such as breast cancer. We discovered that
pretreatment of breast cancer cell lines with epidermal growth factor (EGF) effectively
blocked drug and death receptor induced apoptosis. This protection from apoptosis is
mediated by a serine threonine kinase called AKT through up-regulation of the Bcl-2
anti-apoptotic family member Mcl-1. Besides breast cancer, we have found that a lipid,
lysophosphatic acid (LPA) blocks apoptosis in chronic lymphocytic leukemia (CLL)
cells using a similar mechanism. We are currently investigating the regulatory elements
controlling Mcl-1 expression.
Molecular-based therapies could alter the balance between cell death and survival
towards killing cancer cells. Tumor necrosis factor related apoptosis-inducing ligand
(TRAIL) selectively kills cancer cells while normal cells are resistant to TRIAL-induced
apoptosis. In collaboration with Dr. James Johnston, we are investigating the potential of
TRAIL as a therapy for chronic lymphocytic leukemia (CLL) alone or in combination
with chemotherapy.
62
In addition, we previously discovered that chemotherapeutic drugs increase TRAIL death
receptor (DR4/5) expression and this contributes to drug-induced apoptosis. We are
defining the regulatory elements controlling DR4/5 expression in CLL cells to enhance
the clinical effectiveness of TRAIL.
The goal of this research is to define the signal transduction pathways leading to cell
death or survival. This will elucidate pharmaceutical targets that could alter the cellular
balance in favour of cell death. This research will be the foundation to establish clinical
trials using molecular targeted therapies to increase effectiveness of chemotherapy in
cancer.
Publication since 2006
1. Seftel, M.D.,Demers, AA, Banerji, V., Gibson, SB, Musto, G., Pitz, , MW, and
Johnston, JB 2009 Chronic Lymphocytic Leukemia (CLL) and Small Lymphocytic
Lymphoma (SLL) Diagnosed by Immunophenotyping: Population Based Incidence
and Outcome. Leukemia Research In press
2. Chinnadurai, G. and Gibson S.B. 2009 BNIP3 subfamily BH3-only proteins mitochondrial stress sensors in normal and pathological functions. Oncogene In press
3. Eisenstat DD and Gibson SB 2009 RIGging functional outcomes in glioma cells:
New insights into LRIG proteins in malignant gliomas Cancer Biology and Therapy
Commentary In press.
4. Amerin, L, Panasci, L., Gibson S.B., Johnston, J.B., Soulieres D., and Aloyz A.
(2009) Primary del 17 chronic lymphocytic leukeamia lymphocytes are
hypersensitive to dasatinib in vitro. Br. J. Heamol. In press
5. Kumar, S.A., Hu, X., Brown M., Kuschak, B., Hernandez, T. A., Johnston, J.B., and
Gibson, S.B. 2009 Lysophosphatidic Acid (LPA) receptor expression in chronic
lymphocytic leukemia leads to cell survival mediated by VEGF. Leukemia and
Lymphoma In press
6. Burton, T, Eisenstat, D. D. and Gibson S.B. 2009 Bcl-2 Nineteen kilodalton
Interacting Protein (BNIP3) acts as transcriptional repressor of Apoptosis Inducing
Factor (AIF) expression preventing cell death in human malignant gliomas. J.
Neuroscience 29:4189-99.
7. Burton, T. and Gibson, S. B. 2009 The role of Bcl-2 family member BNIP3 in cell
death and disease: NIPping at the heels of cell death. Cell Death and Differentiation
16:515-23.
8. Begleiter, A., Hewitt, D., Gibson S.B., and Johnston J.B. 2009 An NQO1
polymorphism as a risk and prognostic factor for chronic lymphocytic leukemia.
Leukemia Research 33(1):74-81
9. Chen, Y, Azad, M and Gibson, SB 2009 Superoxide is the major reactive oxygen
species regulating autophagy. Cell Death and Differentiation 16:1040-52
10. Azad, M. B., Chen, Y and Gibson S.B. 2008 Regulation of autophagy by reactive
oxygen species (ROS): implications for cancer progression and treatment.
Antioxidant and Redox Signaling Oct 1. [Epub ahead of print]
11. Amrein L., Hernandez, T., Ferrario, C., Johnston, J., Gibson, S.B., Panasci L, and
Aloyz R. 2008 Dasatinib sensitizes primary chronic lymphocytic leukemia
lymphocytes to chlorambucil and fludarabine in vitro Br. J. Heamatology 143:698706.
63
. Chen Y., McMillian Ward E., Kong, J., Isreals S. J. and Gibson S. B. 2008 Oxidative
stress induces autophagy and contributes to cell death independent of apoptosis in
cancer and transformed cells. Cell Death and Differ. 15:171-82
. Henson, E. S., Johnston, J. B., and Gibson S. B. 2008 The role of TRAIL and its death
receptors in the treatment of hematological malignancies. Leukemia and Lymphoma
49:27-36
. Azad M. B., Chen Y., Henson E. S., McMillian Ward E., Israels S. J., and Gibson S. B.
2008 Hypoxia induces autophagic cell death in a poptosis-competent cancer cells.
Autophagy 4:195-204
. Chen, Y., Gibson, S. B. 2008 Mitochondria generation of reactive oxygen species is a
trigger for autophagy? Autophagy 4:246-8
. Klinosky D., et al 2008 Guidelines for the use and interpretation of assays for
monitoring autophagy in higher eukaryotes. Autophagy 4:151-75
. Hu X., Sun, J., Johnston J.B. and Gibson S.B. 2008 Lysophosphatidic acid (LPA)
induces the expression of Vascular Endothelial Growth Factor (VEGF) leading to cell
survival in hematopoietic malignancies. Cellular Signaling 20:1198-208.
. Mendoza, F. J, Ishdorj, G., Hu, X., and Gibson, S. B. 2008 Death receptor-4 (DR4)
expression is regulated by transcription factor NF-kB in response to etoposide
treatment. Apoptosis 13:759-70
. Ishdorj, G., Graham, B., Hu, X., Johnston, J. B., Chen, J., Fang, X., and Gibson, S. B.
2008 Lysophosphatidic acid ( LPA) protects cancer cells from HDAC inhibitor
induced apoptosis mediated by histone deacetylase (HDAC)activation. J. Biol. Chem.
283:16818-29
. Ghavami S., Asoodeh A., Klonisch T., Halayko A. J., Gibson, S. B., Booy E., NadriManesh H., and Los M. 2008 Brevinin-2 R semi-selectively kills cancer cells by a
distinct mechanism which involves the lysosomal-mitochondrial death pathway. J.
Cell. Mol. Med. 12:1005-22
. Maddika S., Bay G. H., Kroczak T. J., Ande, S., Maddika S., Wiechec E., Gibson S.
B., and Los M. 2007 Akt is transferred to the nucleus in cells treated with apoptin and
it participates in apoptin induced cell death. Cell Proliferation 40:825-837
. Wafa K., Wong K., Ma G., Gibson S. B., and El-Gabalawy H. 2007 Regulation of
Apoptosis in Fibroblast-like Synoviocytes by the Hypoxia-Induced Bcl-2 Family
Member BNIP3 Arthritis Rheum. 2007 56:2854-63
. Chen Y., McMillian Ward E., Kong, J., Isreals S. J. and Gibson S. B. 2007 Inhibition
of complex I and II of the electron transport chain selectively induces autophagy
contributing to cell death mediated by r eactive oxygen species (ROS). J. Cell Sci.
120:4155-66
. Henson, E. S., Johnston, J. B., Los, M., and Gibson S. B. 2007 Clinical outcomes of
epidermal growth factor receptor family inhibitors in breast cancer. Biologics:
Targets and Therapies 3:229-39
. Henson, E.M., and Gibson S.B. 2006 Epidermal Growth Factor and cell survival
implications for targeted cancer therapy. Cellular Signaling 18:2089-97.
. Burton, T.R., Henson, E.S., Baijal, P., Eisenstat, D.D. and Gibson, S.B. 2006 The procell death Bcl-2 family member, BNIP3, is localized in the nucleus of human glial
cells: Implications for glioblastoma multiforme tumor cell survival under hypoxia. Int.
J. Cancer 118:1660-9
27. Henson, H.S., Hu, X., and Gibson, S.B. 2006 Herceptin sensitizes ErbB2 (Her2/neu)
over expressing cells to apoptosis by reducing anti-apoptotic Mcl-1 expression.
Clinical Cancer Research 12:845-53.
Invited Seminars and Presentations at Symposia/Meetings
1. Department of Pharmology and Toxicology, University of Manitoba, March 2009
2. Department of Pathology, University of Calgary, September, 2008
3.
Georgia Medical School, Augusta GA, November, 2007
4.
Winship Cancer Institute, Emory University, Atlanta, GA, November, 2007
5. Updates in CLL Conference, Ontario Cancer Institute, Toronto, ON, November 2007
6. Karmanos Cancer Institute, Wayne State University, School of Medicine, Detroit MI,
April 2007
7. Department of Medical Genetics, University of Calgary, Calgary, AB, March 2007
8.
Division of Hematology, Mayo Clinic, Rochester, MN March 2007
9.
Department of Oncology, Queens University, Kingston, Ontario, January 2007
10. Ontario Cancer Institute, Princess Margaret Hospital, April, 2006
11. Human Genome Sciences Inc., Gaithersburg, MB, June, 2006
12. American Society for Hematology, Orlando, 2006
11. NCIC CTG Annual Fall Meeting, Montreal, 2006
12. National CLL Meeting, Winnipeg, Canada, November, 2006
Professional Service
1.
Interim, Provincial Director, Research, CancerCare Manitoba
2.
Administration
3.
Director of Translational Research
4.
Scientific Director of the Manitoba CLL Tissue Bank
5.
Radiation Safety Officer for Manitoba Institute of Cell Biology
6.
Attend Manitoba Institute of Cell Biology Senior Investigator Meetings
7.
Attend Departmental Council Meetings
8. Organizer of Signal Transduction Journal Club
9. Administrator of the Invited Speakers Program- Molecular Biology series
10. Member of Standard Operating Practices Committee at Manitoba Institute of
Cell Biology
11. Attended workshops on PCR techniques and Laboratory Animal Care and Use.
12. Attended the National Cancer Research Initiative meeting for Young
Investigators representing Manitoba.
13. External Reviewer for the Saskatchewan Health Research Foundation for
Establishment grant.
External Service:
1. Reviewer for manuscripts for peer-reviewed scientific journal: Oncogene,
Molecular Biology of the Cell, Blood, Cancer, Cancer Research, British Journal
of Cancer, Cell Death and Differentiation and Carcinogenesis,
2. Participated in a teleconference to nominate members of the Cancer A and B
grant committees for Canadian Institutes of Health Research
3.
Reviewer for grant submitted to the Alberta Heritage Foundation
65
Member of External Committees
NCIC Personnel Awards Committee
2008-present
Leukemia and Lymphoma Society of Canada
2007-present
Grant Panel Member
Lymphoma Foundation of Canada
2006-present
Scientific Advisory Board
National Institutes of Health,
2006-present
BMCT Study Section Committee member
NCIC CTG, Correlative Science
2006-present
Hematology Committee member
Canadian Institutes of Health Research
2005-present
New Investigator committee (NIA)
National Cancer Institute of Canada
Health Research Ethics Board
2005-present
Functional Analysis of the Mammalian Genome
Now that the human genome has been decoded, the next major challenge to the Genome
Initiative will be to bridge the gap between these rapidly expanding DNA sequence
databases and gene function. To utilize the sequence information for large-scale functional
studies, we have developed a process called tagged-sequence mutagenesis to disrupt genes
expressed in mouse embryo-derived stem (ES) cells and to characterize each mutation by
direct DNA sequencing. Comparison of these sequence tags (PSTs) with the existing
databases identifies disruptions of known genes or genes which may be related by
homology or functional domains. The ability to induce, characterize and maintain
mutations in ES cells circumvents many limitations associated with conventional
mammalian genetics, and will greatly increase the number of mutant alleles (typically loss
of function mutations) by which gene functions can be studied in mice and in cell lines
derived from such mice. The process will facilitate a functional analysis of a mammalian
genome in vivo and will provide animal models for human genetic diseases. Our initial
goal is to develop an Embryonic Stem Cell Library of 20 - 40,000 defined gene mutations.
ES cell clones containing specific mutations in genes of interest will be made available to
investigators as a national resource.
Functional Analysis of TLS, EWS, and ALR in Normal Development and in
Oncogenic Transformation
Mutations (from the ES cell library) transmitted to the germline will focus on genes
known or suspected to be involved in tumor progression. Understanding the normal
function of a gene in mammalian development is a powerful approach to understanding
how the oncogene contributes to the respective cancer. The focus of the lab is on genes
which are translocated in the development of human cancers; specifically, the TLS, EWS
and ARL genes. While the translocations and the associated cancers for these genes are
highly characterized, little is known about function of the genes themselves or how they
contribute to tumor development. Our approach is to analyze developmental defects in
mice that are deficient for each specific gene (and are otherwise genetically identical to
wild-type mice). For example TLS is a gene that is translocated in many human soft tissue
sarcomas and myelogenous leukemia. Functional analysis of mice that are homozygous
for the TLS/FUS mutation has revealed TLS plays a critical role in embryogenesis. We are
now in a position to examine the function of this gene as it directly relates to the diseased
or cancerous state found in humans. Furthermore, we have derived cell lines from the TLS
deficient mice that will enable a molecular analysis of the TLS protein, the proteins it
interacts with, its regulatory mechanisms, and the signaling pathways it is involved in.
67
Publications Since 2006
1.
2.
3.
4.
5.
Xie Y, Yang H, Pan J, Miller JH, Shih DM, Hicks GG, Xie J, Shiu RPC.
(2008). Cells deficient in oxidative DNA damage repair genes Myh and Ogg1 are
sensitive to oxidants with increased G2/M arrest and multinucleation.
Carcinogenesis, 29:2432.
Cann, KL., Hicks, GG. (2007) Regulation of the cellular DNA double-strand
break response. Biochemistry And Cell Biology -biochimie Et Biologie
Cellulaire, 85: 663-674.
Cann, KL., Klewes, L., Bosc, DG., and Hicks, GG. (2006). Absence of an
Immediate G1/S Checkpoint in Primary MEFs Following g-Irradiation Identifies a
Novel Checkpoint Switch. Cell Cycle 5:1823-1830
Law WJ, Cann KL and Hicks GG. (2006). TLS, EWS and TAF15: A Model for
Transcriptional Integration of Gene Expression. Brief Funct Genomic
Proteomic., 5:8-14.
Nord AS, Chang PJ, Conklin BR, Cox T, Harper CA, Hicks GG, Huang CC, Johns
SJ, Kawamoto M, Liu S, Meng EC, Morris JH, Rossant J, Ruiz P, Skarnes WC,
Soriano P, Stanford WL, Stryke D, von Melchner H, Wurst W, Yamamura K,
Young SG,, Babbitt PC, and Ferrin, TE, (2006) The International Gene Trap
Consortium Website: a portal to all publicly available gene trap cell lines in
mouse. Nucleic Acids Res., 34:D642-648.
Chapters and Invited reviews
1. Cann K and Hicks GG. (2007). Regulation of the Cellular DNA Double-Strand
Break Response. Biochem. Cell Biology, 85:663-674.
2. The International Mouse Knockout Consortium. (2007). A Mouse for All
Reasons. Cell 128: 9-13
3. Jane Qiu. (2006) Mighty mouse. Nature 444: 814-816.
4. David Grimm. (2006). A mouse for every gene. Science 312: 1862–1866.
Invited Seminars and Presentations at Symposia/Meetings
1. The North American Conditional Mouse Mutagenesis Program (NorCOMM)
Functional Annotation of the Mammalian Genome Conference, Banff 2009.
2. “Genetic Modeling of Disease in ES cells.” CIHR Canadian Student Health
Research Forum on Stem Cells, Winnipeg, June 2008.
3. High Throughput Targeting in Embryonic Stem Cells.” Human Protein Interaction
Initiative Workshop, Ottawa, June 2008.
4. “A functional role for the TLS proto-oncogene in DNA damage response.”
University of Alberta, May 2008.
5. “NorCOMM: High Throughput Mammalian Functional Analysis for the Discovery
of Novel Determinants of Human Disease.” International Knockout Mouse
Consortium Meeting, Toronto, May 2008.
6. “High throughput approaches to genetic modeling of disease in ES cells.” EastWest Alliance and Cambridge Cancer Research Institute, Cambridge UK, April
2008.
7. “Genetic Model Organisms.” Italian National Research Council (CNR) - Genome
Canada Workshop, Rome, April 2008.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
“Stem Cells.” Sanofi-Aventis Biotechnology Challenge Keynote Speaker,
Winnipeg, April 2008.
“NorCOMM Gene Trap Program.” Texas Institute of Genomic Medicine, Houston,
March 2008.
“International Knockout Mouse Consortium: High throughput gene targeting in ES
cells.” Mon-Man International Symposium, Melbourne, February 2008.
“High Throughput Mammalian Functional Analysis for the Discovery of Novel
Determinants of Human Disease.” Functional Annotation of the Mouse Genome,
Munich, January 2008.
“U3 Promoter Gene Trapping,” “High Throughput Gene Targeting,” and “Genome
Outreach: Engaging the Canadian Scientific Community.” NorCOMM AGM,
Toronto, May 2007.
“Federation of International Mutant Mouse Resource: Analysis of world wide
distribution networks.” International Knockout Mouse Consortium Workshop,
Brussels Belgium, February 2007.
“NorCOMM: High Throughput Mammalian Functional Analysis for the Discovery
of Novel Determinants of Human Disease.” International Knockout Mouse
Consortium Workshop, Brussels Belgium, February 2007.
“NorCOMM: High Throughput Mammalian Functional Analysis for the Discovery
of Novel Determinants of Human Disease.”
Great Lakes Development
Symposium, Toronto, February 2007.
“Mouse Modeling in Pathogenomics.” Pathogenomics and Innate Immunity
International Workshop, Wellcome Trust Sanger Centre, Cambridge UK, January
2007.
European Conditional Mouse Mutagenesis Program Workshop. Invited
participant, Munich, Germany, January 2007.
“Pre-Clinical Mouse Models for Arthritis.” Canadian Arthritis Network Annual
Scientific Conference, Winnipeg, December 2006.
“Developing Pre-Clinical Mouse Models for Disease.” Flanders Medical Centre,
Adelaide Australia, November 2006.
“Knock out mouse models for studying disease.” International Centre for Infectious
Diseases Research and Innovation Symposium, Winnipeg, October 2006.
“NorCOMM: High Throughput Mammalian Functional Analysis for the Discovery
of Novel Determinants of Human Disease.” World Congress of Psychiatric
Genetics, Cagliari Italy, October 2006.
“Development of a high-throughput gene targeting pipeline.” Centre for Modeling
of Human Disease Workshop, Toronto, June 2006.
“International Coordination of Mutant Mouse Resources.” 3rd FIMRe International
Workshop, Tsukuba Japan, May 2006.
“Mouse Modeling for Human Disease.” CSMLS 2006 National Congress,
Winnipeg, May 2006.
Canadian Genetic Diseases Network Scientific Symposium. Quebec, April 2006.
69
Professional Service
1.
Canadian Genetic Disease Network Centre of Excellence Investigator. 2000-2008
2.
NIH Ewing Sarcoma Initiative. 2002-present
3.
International Gene Trap Consortium. 1999-present
4. International Mouse Mutagenesis Consortium. 2001-present
5. International Knockout Mouse Project Consortium. 2004-present
6.
Federation of International Mutant Mouse Resources. 2005-present
7. Canadian Mouse Consortium, founding member. 2004-present
8. International Knockout Mouse Consortium, founding member. 2004-present
Professional Activities
1. Director, Mammalian Functional Genomics Centre. 1999-present
2. Canadian Institutes of Health Research, Reviewer for G, CPT and MCC Panels.
1999-present
3. Chair, CIHR Institute of Genetics New Principal Investigator Symposium. 2001present
4. Scientific Director, Gene Modeling Centre, University of Manitoba. 1999present
5.
Scientific Advisory Board Member, Genome BC, Pathogenomics of Innate
Immunity. 2006-present
6.
CIHR Institute of Genetics Advisory Panel. 2001-present
7. Scientific Advisory Board Member, Genome Quebec, Gene Regulators in
Disease. 2006-present
8. Scientific Advisory Board Member, BC Transgenics Centre. 2007-present
9. Scientific Director, Genetic Modeling Centre, University of Manitoba. 2007present
10. Manitoba Health Research Council, Research Advisory Committee. 2008present
Elevated homocysteine levels are associated with increased risk of atherosclerotic
vascular disease and of venous thrombosis. We have shown that homocysteine induces
expression of tissue factor, the trigger for the coagulation cascade, by human monocytes.
This is a plausible explanation for the thrombotic tendency associated with homocysteine,
which we are now looking to confirm in patient studies. We are also investigating the
biochemical mechanism by which homocysteine activates the monocytes, which may
have important implications for the management of hyperhomocysteinemia. A second
area of interest is the laboratory assessment of hemostasis and thrombophilia.
Publications Since 2006
1. Zarychanski, R., Houston, D.S. (2008) Anemia of chronic disease: is it an adaptive,
beneficial response? Can. Med. Assoc. J. 179, 333-337.
2. Skrabek, PJ; Houston, D.S. (2008) Hyperferritinemia: An Unexpected Effect of
Treatment with Danazol. Blood. 112, 1312-1312
3. Zarychanski.R, Doucette. S, Fergusson. D, Roberts. D, Houston D.S., Sharma. S,
Gulati. H, Kumar. A . (2008) Early intravenous unfractionated heparin and mortality
in septic shock. Critical Care Medicine. 36, 2973-2979.
4. Zarychanski, R; Houston, DS. (2008). A harmful disorder or an adaptive, beneficial
response? Canadian Medical Association Journal. 179, 449-449
71
Our platelet research laboratory studies basic mechanisms of platelet function and
investigates patients with inherited platelet function abnormalities, in conjunction with the
clinical Haemostasis Laboratory. Our projects include: 1) Investigating the role of CD63,
a member of the tetraspanin superfamily present on platelet dense granule and lysosomal
granule membranes, and expressed on the platelet surface following activation, where it
associates with the platelet integrin alphaIIb/beta3, and with the contractile platelet
cytoskeleton. It plays a role in platelet spreading on adhesive surfaces. We are presently
investigating how it modulates integrin-mediated signaling. Understanding the role of
CD63 has implications beyond platelet function, as it, and similar molecules, may be
involved in tumor cell migration and metastases. 2) Studies of patients with inherited
platelet function disorders, with a particular interest in families with a congenital
deficiency of platelet dense granules, Storage Pool Deficiency. 3) Studies of the platelet
defect in patients with Noonan Syndrome. 4) In collaboration with colleagues at the
Toronto Hospital for Sick Children, we have created a national registry of patients with
inherited platelet disorders, an opportunity to improve our understanding of these rare
conditions, aid in their diagnosis, and evaluate treatment options.
Publications Since 2006
Refereed Journal Articles
1. Israels SJ, McMillan-Ward EM.
supports the association of tetraspanin
CD63 with CD9 and integrin IIb 3 in activated platelets (2009). Thromb Res. (In
press).
2. Halton J, Gaboury I, Grant R, Alos N, Cummings E, Matzinger M, Nazih S, Lentle B,
Sharon Abish S, Atkinson S, Cairney E; Dix D, Israels S, et al. Advanced vertebral
fracture among newly diagnosed children with acute lymphoblastic
Leukemia: Results of the Canadian steroid-associated osteoporosis in the pediatric
population (STOPP) (2009) J Bone Min Res. (In press).
3. Hayward CPM, Moffat KA, Spitzer E, Timleck M, Plumhoff E, Israels SJ, White
J. Results of an external proficiency testing exercise on platelet dense granule
deficiency testing by whole mount electron microscopy (2009) Am J Clin Path. 131:
671-675.
4. Israels SJ. Diagnostic evaluation of platelet function disorders in neonates and
children: an update (2009). Sem Thromb Hemost. 35(2): 181-188
5. McNicol A, Israels SJ. (2008). Beyond Hemostasis: the role of platelets in
inflammation, malignancy and infection. Cardiovasc Hematol Dis–DT. 8, 99-117.
72
6. Chen Y, McMillan-Ward E, Kong J, Israels SJ, Gibson SB. (2008). Oxidative stress
induces autophagic cell death independent of apoptosis in transformed and cancer
cells. Cell Death Diff. 15, 171-82.
7. Azad MB, Chen Y, Henson ES, Cizeau J, McMillan-Ward EM, Israels SJ, Gibson SB.
(2008) Hypoxia induces autophagic cell death in apoptosis-competent cells through a
mechanism involving BNIP3. Autophagy. 4, 195-204.
8. Chen Y, McMillan-Ward E, Kong J, Israels SJ, Gibson SB. (2007). Mitochondrial
electron transport chain inhibitors of complexes I and II induce autophagic cell death
mediated by reactive oxygen species. J Cell Sci. 120, 4155-66.
9. McNicol A, Eyer E, Jackson ED, Israels SJ. (2007). A role for von Willebrand factor
in Streptococcus sanguis-induced platelet activation. Thromb Haemost. 98, 1382-84.
10. Israels SJ, McMillan-Ward EM. (2007). Platelet tetraspanin complexes and their
association with lipid rafts. Thromb Haemost. 98, 1081-87.
11. Israels SJ, Michelson AD. (2006) Anti-platelet therapy in children. Thromb Res. 118,
75-83.
. Feldman B M, Pai M, Rivard G E, Israels S, Poon M-C, et al. (2006). Tailored
prophylaxis in severe Hemophilia A: Interim results from the first 5 years of the
Canadian Hemophilia Primary Prophylaxis Study. J Thromb Haemost. 4, 1228-36.
Rand M, Israels SJ, McNicol A (2009). Platelet Structure and Function. In:
Mechanisms in Hematology, 4th Ed. (In press).
Israels SJ. (2007) Inherited abnormalities of fibrinogen. eMedicine Journal [serial
online]. Available at: www.emedicine.com/ped/topic#3042.htm,
Israels SJ. (2007) Factor VII deficiency. eMedicine Journal [serial online]. Available
at: www.emedicine.com/ped/topic#3041.htm,
Israels SJ. (2007) Factor XIII deficiency. eMedicine Journal [serial online]. Available
at: www.emedicine.com/ped/topic#3040.htm,
Israels SJ. (2007) Platelet Function in the Newborn. In: Platelets, Second Edition
(Michelson AD, ed). Academic Press. pp. 431-42.
Israels SJ, Schwetz N, Boyer R, McNicol A. (2006) Bleeding disorders:
characterization, dental considerations and management. J Can Dent Assoc. 72, 827a827l.
Hang MX,. Blanchette V, Pullenayegum E, Babyn P, Card R, Chan A, Demers C, Gill
K, Israels S, Klaassen R, Laferriere N, Lillicrap D,. Luke , McLimont M.. Risk factors
of bleeding severity in young boys with severe hemophilia a on tailored prophylaxis:
long-term (10-year) results from the canadian hemophilia primary prophylaxis study.
Congress ISTH July 2009.
Blanchette VS, Babyn P, Card R, Chan A, Demers C, Gill K, Israels S, Klaassen R,
Laferriere N, Lillicrap D, Luke KH, McLimont M, et al. Long Term (10 year) results
from the Prospective Canadian hemophilia dose escalation prophylaxis trial.
Sinclair GD, Blanchette V, Card RT, Chan AKC, Israels SJ, Lillicrap D, Rivard Get al.
Does heterogeneity in measured calibrated thrombin generation assay or FVIII activity
(<1%) explain clinical heterogeneity in severe hemophilia A? Congress ISTH July
2009.
73
4. Israels SJ, McMillan-Ward EM. Palmitoylation supports the association of tetraspanin
CD63 with CD9 and the activated platelet cytoskeleton. Int. Soc. Thromb. Hemost.
Congress , July 2009.
5. Grant R, Halton J, Abish S, Barr R, Cairney E, Dix DB, Fernandez C, Israels S, Lewis
V, et al., and the Canadian STOPP Consortium. Osteoporosis screening in childhood
acute lymphoblastic leukemia. A first step in understanding the natural history of
vertebral compression. Am Soc Pediatr Hematol/Oncol meeting. Cincinnati. May,
2008.
6. Halton J, Abish S, Barr R, Cairney E, Dix DB, Fernandez C, Grant R, Israels S, Lewis
V, et al. and the Canadian STOPP Consortium. The relationship between bone lumbar
spine bone mineral density and vertebral consortium at leukemia diagnosis. Am Soc
Pediatr Hematol/Oncol meeting. Cincinnati. May, 2008.
7. Blanchette VS, Rivard GE, Pai MK, Israels SJ, McLimont M, Feldman BM. 10 year
musculoskeletal outcomes with tailored primary prophylaxis:
the Canadian
Hemophilia Prophylaxis Study. American Society of Hemoatology, Dec 2007 Blood
2007;110:341a.
8. Schwetz N, Jacobson R, Israels SJ. Improving communication and supporting
efficient product use with electronic recording. ISTH, Geneva July 2007; J Thromb
Haemost, 2007;(Suppl2):5.
9. Israels SJ, McMillan-Ward EM. The association of platelet tetraspanin complexes
with lipid rafts. Gordon Research Conference: Platelet and Megakaryocyte Biology
Ventura, Calif, March 2007.
10. Israels SJ, McMilllan-Ward EM. Platelet tetraspanin complexes and their relation to
lipid rafts. American Society of Hematoloogy, Dec 2006; Blood 2006;108: 440a
11. Schwetz N, Jacobson R, Israels S J. Electronic recording: a useful tool for improved
communication and monitoring of patient adherence. World Federation of Hemophilia,
Vancouver June 2006; Haemophilia 2006.
12. Schwetz N, Jacobson R, Israels SJ, Houston D, Woloschuk DMM. Telehealth: A tool
for patient assessment and distance education in a regional bleeding disorders
program. Vancouver June 2006; Haemophilia 2006.
Invited Seminars and Presentations at Symposia/Meetings
1.
“Algorithm for evaluation of platelet dysfunction in children.” Canadian Pediatric
Thrombosis and Hemostasis Network, Ottawa, ON, May 8, 2009.
2. “Von Willebrand Disease: Common disease (?), difficult diagnosis (!)”. Department
of Pediatrics & Child Health Grand Rounds, University of Manitoba Pediatric Grand
Rounds. December 11.
3. “Assessment of Bleeding in Infants and Children”. Department of Family Medicine,
University of Manitoba, Winnipeg, Manitoba, October 31, 2008.
4. “Pediatrics – Little People Have Blood Too”. Meet the Hematologist. CancerCare
Manitoba, October 21, 2008.
5. “Evaluation of the Child with a Suspected Bleeding Disorder”. Pediatric Hemostasis
& Thrombosis Update 2008, University of Toronto, Toronto, Ontario, October 3-4.
Workshop Session I.
.
“Transfusion for Oncology Patients”. Department of Pediatrics & Child Health.
CK5 Oncology Orientation. Basic Hematology/Oncology. Ann Thomas Building,
Children’s Hospital. August 8, 2008.
.
“How to assess platelet function”. Eastern Canada Hemostasis fSymposium. St.
John’s Newfoundland. Sept. 19, 2008.
. “Macrothrombocytopenia associated with 22q11.2 deletion syndrome” Association
of Hemophilia Clinic Directors of Canada Annual Meeting, Saskatoon,
Saskatchewan. May 3, 2008.
.
“Bleeding Disorders 101” The Canadian Hemophilia Society Workshop. Winnipeg,
January 26, 2008
. “Platelet function testing – Myths” Dalhousie University Hematology Symposium,
Halifax, September 29, 2007
. “Children with cancer: not just little adults” CANO Conference. Winnipeg, March
17, 2007.
12. “Inherited platelet disorders” Pediatric Hemostasis & Thrombosis Update.
Department of Paediatrics, Faculty of Medicine, University of Toronto. September
29, 2006
13. “Laboratory diagnosis of platelet abnormalities” Pediatric Hemostasis & Thrombosis
Update. Department of Paediatrics, Faculty of Medicine, University of Toronto.
September 30, 2006
14. “What is unique about childhood cancer?” Canadian Society of Laboratory
Technologists Congress, Winnipeg, May 2006.
Professional Service
University of Manitoba
1. Section Head, Pediatric Hematology/Oncology/BMT, 1993-present
2. Faculty of Medicine Promotion Committee, 2006-present
3.
Dept of Pediatrics and Child Health Promotions Committee: Chair, 2004-present
4.
Department of Pediatrics Executive and Planning Committee, 1997-present
5. Hematology/Medical Oncology Fellowship Training Program Committee, 1994present
WRHA
1. Director, Haemostasis Laboratory, Health Sciences Centre 1994-present
CancerCare Manitoba
1. CCMB LG Israels Memorial Lecture Committee, 2004-present
2. CCMB Medical Council, 2004-present
3. Simon and Sarah Israels Thesis Prize Review Committee: Chair, 2004-present
4. CancerCare Manitoba Foundation Board of Directors, 2003-present
5. CancerCare Manitoba Foundation Project Grants and Awards Committee, 2003present
75
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.
.
.
External Review: Division of Pediatric Hematology/Oncology, The Hospital for Sick
Children, Toronto, March 2009.
Editor, Mechanisms in Hematology, 4th Edition.
External Review: Division of Pediatric Hematology/Oncology, Department of
Pediatrics, University of British Columbia, Vancouver, October 2006.
Canadian Council of Pediatric Hematology/Oncology Program Directors Executive
Committee, 2005-present
Royal College of Physicians and Surgeons – Specialty Committee (Nucleus) in
Pediatric Hematology/Oncology, 2004-present
Royal College of Physicians and Surgeons – Pediatric Hematology / Oncology
Examination Committee, 2005-present
External Grant Reviews: Heart and Stroke Foundation of Canada, CIHR, Canadian
Blood Services/Bayer, Health Sciences Centre Research Foundation, C17 Research
Network
Journal Reviews: Blood, J. Thrombosis and Haemostasis, Thrombosis and
Haemostasis, J. Pediatric Hematology/Oncology, Pediatric Research, J. Pediatrics,
Thrombosis Research
My primary research interest is in chronic lymphocytic leukemia (CLL) and I am involved in a
number of translational research programs related to this disease. These studies involve the
epidemiology and basic science of CLL, in addition to clinical trials. To further these
activities, we have developed the CLL Clinic at CancerCare Manitoba and the Manitoba CLL
Tumor Bank, which is housed in the MICB. Our epidemiological studies have demonstrated
that the incidence of CLL is much higher than previously reported with elderly male patients
having a particularly poor prognosis. Our ongoing laboratory studies are evaluating new
therapies and prognostic markers in CLL and examining the effects of age and gender on the
biology of this cancer.
Publications Since 2006
1. Amrein L, Panasci L, Gibson S, Johnston JB, Soulieres D, and Aloyz, R. Primary del 17
chronic lymphocytic leukaemia lymphocytes are hypersensitive to dasatinib in vitro. Br
J Haematol, (in press).
2. Begleiter A, Hewitt D, Gibson SB, and Johnston JB. Investigation of an NQO1
polymorphism as a possible risk and prognostic factor for chronic lymphocytic leukemia.
Leuk Res, 33:74-81, 2009.
3. Amrein L, Hernandez TA, Ferrario C, Johnston JB, Gibson SB, Panasci L, and Aloyz R.
Dasatinib sensitizes primary chronic lymphocytic leukaemia lymphocytes to
chlorambucil and fludarabine in vitro. Br J Haematol, 33:74-81, 2009.
4.
Kumar SA, Hu X, Brown M, Kuschak B, Hernandez TA, Johnston JB, and Gibson SB.
Lysophosphatidic acid (LPA) receptor expression in chronic lymphocytic leukemia leads
to cell survival mediated through VEGF expression. Leuk Lymph (In press)
5. Seftel MD., Demers AA, Banerji V, Gibson SB, Hewitt D, Musto G, Pitz MW, and
Johnston JB. Incidence of chronic lymphocytic leukemia (CLL) and small lymphocytic
lymphoma (SLL) diagnosed by immunophenotyping: Population based incidence and
outcome. Leuk Res. Jul 4 [Epub ahead of print]
6. Ishdorj G, Graham B, Hu X, Johnston JB, Fang X, and Gibson SB. Lysophosphatidic
acid (LPA) activates histone deacetylase (HDAC) activity protecting cancer cells from
HDAC inhibitor-induced apoptosis. J Biol Chem, 283:16818-16829, 2008.
7.
Henson ES, Johnston JB and Gibson SB. The role of TRAIL death receptors in the
treatment of hematological malignancies. Leuk Lymph, 49:27-35, 2008.
8.
Hu X, Sun J, Banerji V, Johnston JB, and Gibson SB. Lysophosphatidic acid (LPA)
induces the expression of VEGF leading to protection against apoptosis in B-cell derived
malignancies. Cellular Signaling, 20:1198-1208, 2008.
77
9.
10.
11.
12.
13.
14.
Henson, ES, Johnston, JB, Los, M, and Gibson SB. Clinical activities of the epidermal
growth factor receptor family inhibitors in breast cancer. Biologics: Targets and
Therapy, 1:1-11, 2007.
Banerji V, Johnston JB, Seftel M. The role of hematopoietic stem cell transplantation in
chronic lymphocytic leukemia. Transfusion & Apheresis Science, 37:57-62, 2007.
Johnston JB, Navaratnam S, Pitz MW, et al. Targeting the EGFR pathway for cancer
therapy. Curr Med Chem, 13:3483-3492, 2006.
Kabore AF, Hu X, McCrea K, Sun M, Johnston JB, and Gibson SB. The TRAIL
apoptotic pathway mediates proteasome inhibitor induced apoptosis in primary chronic
lymphocytic leukemia cells. Apoptosis, 13:3483-3492, 2006.
Zarychanski R, Elphee E, Walton P and Johnston JB. Osteonecrosis of the jaw
associated with pamidronate therapy. Am J Hematol, 81:73-75, 2006.
Pitz M, Gibson I, Myers M, and Johnston JB. Isolated pulmonary amyloidosis: A case
report and review of the literature. Am J Hematol, 81:212-213, 2006.
Book Chapters
1. Johnston JB, Seftel M. Gibson SB, Chronic Lymphocytic Leukemia. In: J.P. Greer, J.
Foerster, J. Lukens, F. Paraskevas, G.M. Rodgers, and B.E. Glader (eds), Wintrobe’s
Clinical Hematology, 12th Edition, Baltimore, MD: Williams and Wilkins, 2008.
2. Szwajcer D, Johnston JB, Hairy Cell Leukemia. In: J.P. Greer, J. Foerster, J. Lukens, F.
Paraskevas, G.M. Rodgers, and B.E. Glader (eds), Wintrobe’s Clinical Hematology, 12th
Edition, Baltimore, MD: Williams and Wilkins, 2008.
Invited Seminars and Presentations at Symposia/Meetings
1.
2.
3.
4.
5.
6.
Hernandez TA, Hewitt D, Seftel M, and Johnston JB. The improved survival of women
versus men in chronic lymphocytic leukemia may be partially related to IgVH
mutational status. American Assoc Cancer Res., Abstract #2210, 2008.
Ishdorj G, Graham, B, Hu, X, Johnston, JB, and Gibson, SB. Lysophosphatidic acid
(LPA) protected cancer cells from histone deacetylase (HDAC) inhibitor-induced
apoptosis through alteration regulation of histone acetylation. American Assoc Cancer
Res, Abstract #2675, 2008
Johnston JB. The Epidemiology of Chronic Lymphocytic Leukemia. Western
Lymphoma Group Meeting. Banff, May 2008.
Gibson SB, Hu X, Banerji V, Sun J, and Johnston JB. The vascular endotherlial growth
factor (VEGF) autocrine signaling survival pathway is mediated by lysophosphatidic
acid (LPA) induced NFkappaB activation in CLL. The XII International Workshop on
CLL. Leuk Lymphoma, 48:Suppl 1, Abstract P 2.24, 2007.
Begleiter A, Hewitt D, Sivananthan K, Merluza JA, Kuschak BC, Hernandez TA,
Gibson SB, and Johnston JB. NAD(P)H:quinoneoxidoreductase 1 (NQO1)
polymorphism as a risk and prognostic factor for CLL. The XII International Workshop
on CLL. Leuk Lymphoma, 48:Suppl 1, Abstract P 1.13, 2007.
Reiman T, Finch D, Chua N, White D, Stewart DA, van der Jagt R, Johnston JB, Prasad
A, Schwarz H, Zeldis J, and Belch AR. First report of a phase II clinical trial of
lenalidomide oral therapy for peripheral T-cell lymphoma. Blood, 110:Abstract #2579,
2007.
7.
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10.
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12.
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15.
16.
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18.
19.
Banerji V, Hu, X, Sun, J-M, Johnston, JB, Gibson, SB. The vascular endothelial
growth factor (VEGF) autocrine signaling survival pathway iks mediated by
lysophosphatidic acid (LPA) induced NFkappaB activation in B-cellderived
malignancies. American Assoc Cancer Res (in press) 2007.
Hu X, Johnston JB, and Gibson SB. Vascular endothelial growth factor (VEGF)
autocrine survival signaling pathway is regulated by lysophosphatidic acid. 7th
Conference on Signaling in Normal and Cancer Cells, March, 2006.
Hu, X, Sun, J, Johnston, JB, and Gibson, JB. The vascular endothelial growth factor
(VEGF) autocrine survival signaling pathway in chronic lymphocytic leukemia
(CLL) is regulated by lysophosphatidic acid (LPA). Blood, 108:795a, 2006.
Banerji, V, Demers A, Johnston, JB, Pitz, MW, Nugent, Z, Morales, C, Mahmud, S,
Hewitt, D, Gibson, SB, Seftel MD. Younger patients with CLL/SLL are less frequent
and have favorable survival in a Canadian population based study: The Manitoba
Cohort. Blood 108:952a, 2006.
Johnston JB, Kabore AF, McCrea K, Hu X, and Gibson SB. Proteasome inhibition
activates the TRAIL pathway and induces apoptosis in primary chronic lymphocytic
leukemia cells. Proc Amer Assoc Cancer Res, 46:3329, 2005.
Cabral TM, Hewitt D, Maksymiuk A, Johnston JB, Ross D, and Begleiter A. NQO1
polymorphisms as risk factors in colon cancer and chronic lymphocytic leukemia.
Proc Amer Assoc Cancer Res, 46:1158, 2005.
Gibson SB, Graham B, and Johnston JB. Role of NFκB and histone acetylation in the
regulation of death receptor 5 (DR5) expression in chronic lymphocytic leukemia.
The XI International Workshop on CLL. Leuk Lymphoma, 46:Suppl 1, Abstract #71,
2005.
Begleiter A, Cabral T, Hewitt D, Ross DA, Gibson SB, and Johnston JB. NQ01
polymorphisms as risk factors in chronic lymphocytic leukemia. The XI International
Workshop on CLL. Leuk Lymphoma, 46:Suppl 1, Abstract #74, 2005.
Seftel MD, Morales C, Hewitt D, Turner, D, Gibson S, and Johnston JB. High
incidence of CLL/SLL based on immunophenotypic diagnosis: A population based
study. The XI International Workshop on CLL. Leuk Lymphoma, 46:Suppl 1,
Abstract #131, 2005.
Seftel MD, Morales C, Hewitt D, Turner D, Gibson S, and Johnston JB. CLL/SLL is
more common than registry incidence suggests: A population-based study in
Manitoba, Canada. Blood, 106:387a, 2005.
Szwajcer D, Gibson SB, and Johnston JB. The induction of apoptosis by histone
deacetylase inhibition in chronic lymphocytic leukemia (CLL) cells is mediated
through the TNF-related apoptosis-inducing ligand (TRAIL) pathway. Blood,
106:836a, 2005.
McCrea KE, Kabore A, Johnston JB, and Gibson SB. The role of proteasome
inhibitors and the TRAIL apoptotic pathway in the treatment of chronic lymphocytic
leukemia. Blood, 106:334b, 2005.
Graham BA, Kuschak B, Johnston JB, and Gibson, SB. The role of histone
acetylation and death receptor 5 (DR5) expression in the treatment of chronic
lymphocytic leukemia (CLL). Blood, 106:336b, 2005.
79
Professional Services
Assistant Head (Clinical), Manitoba Institute of Cell Biology
Clinical Director, Manitoba CLL Tumour Bank
Cancer Biology Graduate Course Coordinator (36.720) (with Dr. Michael Mowat)
Molecular Biology Course Coordinator for Clinical Hematology/Oncology residents
Chairman for the Planning Committee for the annual Canadian CLL Meeting
Member of the Planning Committee for the annual Canadian Lymphoma Meeting
Coordinator for Hematology/Oncology Section Rounds
Chairman of the LG Israels Annual Memorial Lecture Committee
Manuscript reviewer for Blood, Cancer, Leukemia Lymphoma and Leukemia Research
Scientific reviewer for Alberta Cancer Board
Our research focuses on mechanisms of c-Myc-dependent locus-specific and karyotypic
instability. Our in vitro models include primary, immortalized and tumor cell lines with normal,
experimentally inducible and constitutive c-Myc deregulation, respectively. Our current in vivo
models of c-Myc-dependent genomic instability and neoplasia focus on mouse plasmacytoma.
We were the first to demonstrate that the deregulated expression of the proto-oncogene c-Myc
induces dynamic karyotypic alterations; they include numerical chromosomal changes,
telomere-centromere-fusions and the enhanced formation of extrachromosomal elements (Mai
et al., 1996a). Moreover, we have shown that experimental deregulation of c-Myc mediates
rearrangements, chromosomal and extrachromosomal amplification of specific genes. Among
these genes are dihydrofolate reductase (DHFR), (Mai, 1994; Mai et al., 1996b), CCND2
(cyclin D2) (Mai et al., 1999), ribonucleotide reductase R2 (R2) (Kuschak et al., 1999), and the
carbamoyl-phosphate synthetase-aspartate transcarbamoyl-dihydroorotase (CAD) (Fukasawa
et al., 1997) gene. Other genes, such as syndecan-1 and 2, glyceraldehyde-3-phosphatedehydrogenase, ribonucleotide reductase R1, and cyclin C, remain unaffected irrespective of cMyc protein levels (Mai et al., 1996b). We identified a mechanism that leads c-Myc-mediated
gene amplification. It involves c-Myc-dependent illegitimate locus-specific de novo replication
initiation (Kuschak et al., 2002).
A novel mechanism of c-Myc activation involves c-Myc transcription from extrachromosomal
elements (EEs) (Wiener et al., 1999). Analyses into the functions of EEs have demonstrated
that they carry modified histones and are transcriptional competent. Furthermore, they are able
to replicate their DNA (Smith et al., 2002). c-Myc-induced EEs therefore are functional minichromosomes with the ability to actively contribute to cellular transformation. Our recent work
focuses on the three-dimensional organization of the nucleus and the role of c-Myc in nuclear
remodelling and cell transformation. Highlights are summarized below.
Research Highlights
The three-dimensional (3D) nuclear telomere organization: We undertook a study of normal
cells, of immortalized and primary tumor cells and cell lines to investigate by 3D imaging how
telomeres are organized in the interphase nucleus and whether there was a change in this
organization during cell cycle and during cellular transformation. Telomeres of normal cells
are organized in a cell cycle-dependent manner.
81
occupy a wider nuclear space in G0/G1 and S phases than in the late G2 phase where
are organized into a telomeric disk (TD) first described in Chuang et al., 2004. In
to the ordered organization of non-overlapping telomeres in normal cells,
of tumor cells display an aberrant order and frequently form aggregates (Chuang
al., 2004). We have filed a patent about these findings. It also includes new analytical
.
Analysis of the 3D space occupied by telomeres. To define the 3D nuclear space occupied
telomeres, new software (TeloViewTM ) was developed in collaboration with Dr.
group at the Quantitative Imaging Group, University of Technology, Delft (The
. TeloViewTM allows one to determine the nuclear localization of all telomeres
the interphase nucleus. A detailed summary of the algorithms is described in Vermolen
al., 2005. Recent developments within this program now allow us to determine the
of telomeric aggregates found per nucleus. This ability to quantitatively assess
number of aggregates per nucleus enhances the program features rendering it fully
of the users’ assessment.
-Myc deregulation affects the 3D organization of the nucleus. We have recently found
c-Myc deregulation promotes the formation of telomeric aggregates (TAs). This
change is accompanied by chromosomal rearrangements (CRs) as evident in the
metaphases. We showed that c-Myc mediates the formation of CRs via TAs
positional changes of chromosomes (Louis et al., 2005; Mai and Garini, 2005, Mai
Garini, 2006). Moreover, we have found that chromosomes can alter their positions
as a result of c-Myc deregulation (Louis et al., 2005).
-Myc-dependent formation of telomeric aggregates requires myc boxII. In order to
the Myc-induced formation of telomeric aggregates, we have studied myc
proteins. In wild-type p53 carrying, spontaneously immortalized and nonmouse proB cells (BA/F3) aggregates form only in the presence of wild-type
-Myc deregulation. If myc box II is absent, no such aggregates are observed (Caporali et
., 2007). This finding is directly relevant for c-Myc-dependent tumor formation as only
-type but not myc box II mutant overexpressing cells promote tumor formation in
mice (Fest et al., 2005).
Centromeres reorganize during cellular transformation. The positions occupied by
centromeres in nuclei of mouse lymphocytes vary during the cell cycle and during cellular
transformation (Sarkar et al., 2007). One pathway to this nuclear remodeling involves cMyc deregulation. The impact of this pathway on nuclear organization is currently
explored.
Centromeres reorganize during cellular transformation. The positions occupied by
centromeres in nuclei of mouse lymphocytes vary during the cell cycle and during
cellular transformation (Sarkar et al., 2007). A program to measure centromere positions
in the interphase nucleus was developed by Rahul Sarkar, in collaboration with Dr.
Garini’s group, and patented (Sarkar et al., 2007).
82
impact of this pathway on nuclear organization was demonstrated in recent
. Amanda Guffei in the lab showed in mouse cells that c-Myc deregulation
centromeric nuclear remodeling (Guffei et al., 2007). She also showed that
remodeling leads to the fusion of centromeric ends via their telomeric sequences;
new organization gives rise to Roberstonian translocation chromosomes (Guffei et
., 2007). Her work was featured on the journal cover.
recent Perspectives Article by our group summarizes our current knowledge about
centromere in cell division, speciation and cancer (Silva et al., 2008)
-Myc cooperates with Tip60 to accelerated lymphomagenesis in mice. In
with Bruno Amati, we showed that Tip60 haploinsufficiency and c-Myc
lead to accelerated lymphoma development in mice. Landon Wark in the
was working on this project, which was published in Nature (Gorrini et al., 2007).
instability. I was a guest editor for a special issue in Seminars in Cancer
(February 2007 issue) that featured non-random genomic instability in cancer:
fact, not an illusion. The issue includes articles on mechanisms leading to instability
cancer cells, on modeling of non-random deletions, on large common fragile sites
gene amplification, specificity, selection and significance of gene amplification, on
formation of extrachromosomal elements, on microRNAs and genomic instability,
mechanisms leading to non-random nonhomologous translocations in leukemia, and
the spatial genome organization in the formation of chromosomal translocations.
insights into Hodgkin’s lymphoma. In collaboration with Dr. Hans Knecht
(Sherbrooke, QC), we have gained insights into the biology of Hodgkin’s lymphoma
and shown that the mononucleated Hodgkin cell gives rise to the multinucleated Reed
Sternberg cell through dynamic telomere dysfunction and aberrant cell divisions
(Knecht et al., 2009).
83
since 2006:
Gonzalez-Suarez I, Redwood AB, Vermolen B, Lichtensztejin D, Bhat A, Sullivan T,
Sage J, Stewart CL., Mai S and Gonzalo S. A-type lamins constitute a higher level of
regulation of telomere biology. EMBO J. In press. 2009.
S. Lacoste, E. Wiechec, G. Williams, M. Henriksson, G. Klein, S. Mai. Chromosomal
rearrangements after ex-vivo Epstein-Barr virus (EBV) infection of human B cells.
2009 accepted pending revisions.
I. Bronstein, Y. Israel, E. Kepten, S. Mai, Y. Shav-Tal, E. Barkai, Y. Garini. Transient
anomalous diffusion of telomeres in the nucleus of mammalian cells. Physical
Review Letters, 2009. In press.
Dunn KL, He S, Wark L, Delcuve GP, Sun JM, Yu Chen H, Mai S, Davie JR.
Increased genomic instability and altered chromosomal protein phosphorylation
timing in HRAS-transformed mouse fibroblasts. Genes Chromosomes Cancer
48(5): 397-409. 2009.
Knecht H, Sawan B, Lichtensztejn D, Lemieux B, Wellinger RJ, Mai S. The 3D
nuclear organization of telomeres marks the transition from Hodgkin to ReedSternberg cells. Leukemia. Leukemia. 2009 Mar;23(3):565-73. Epub 2008 Nov 27.
. Mougey V, Kuttler F, Mendis R, Mai S, Fest T. Myc box II mutated alleles promote
genomic instability by impairing c-Myc control of G2 cell cycle phase. Oncogene
accepted pending revision. 2008.
. Silva AGdS, Sarkar R, Harizanova J, Guffei A, Mowat M, Garini Y, Mai S.
Centromeres in cell division, evolution, nuclear organization and disease. J Cell
Biochem. 2008 [E pub ahead of print].
. Tragoolpua K, Intasai N, Kasinrerk W, Mai S, Yuan Y, Tayapiwatana C. Generation of
functional scFv intrabody to abate the expression of CD147. BMC Biotechnology
8:5. 2008.
. Guijon FB, Greulich-Bode K, Paraskevas M, Baker P, Mai S. Premalignant cervical
lesions are characterized by dihydrofolate reductase gene amplification and c-Myc
overexpression: possible biomarkers. J Low Genit Tract Dis. 2007 Oct;11(4):265-72.
. Rak M, Del Bigio MR, Mai S, Westaway D, Gough K. Dense-core and diffuse Abeta
plaques in TgCRND8 mice studied with synchrotron FTIR Microspectroscopy.
Biopolymers. 87(4):207-17. 2007.
. Gorrini C, Squatrito M, Luise C, Syed N, Perna D, Wark L, Martinato F, Sardella D,
Verrecchia A, Bennett S, Confalonieri S, Cesaroni M, Marchesi F, Gasco M,
Scanziani E, Capra M, Mai S, Nuciforo P, Crook T, Lough JW, Amati B. Tip60 is a
haplo-insufficient tumor suppressor required for an oncogene-induced DNA damage
response. Nature 448: 1063-1067. 2007.
. Guffei A, Lichtensztejn Z, Gonçalves dos Santos Silva A, Louis SF, Caporali A, Mai
S. Mouse Robertsonian chromosome formation following c-Myc deregulation.
Neoplasia. 9: 578-588. 2007. Article and journal cover.
. Zakharenko, LP, Kovalenko, L.V., Mai, S. Fluorescence in situ hybridization analysis
of hobo, mdg1 and Dm412 transposable elements reveals genomic instability
following the Drosophila melanogaster genome sequencing. Heredity. 99(5):525-30.
2007. Epub 2007 Jul 11.
84
14. L.P. Zakharenko, L.V. Kovalenko, S. Mai, I.K. Zakharov. Persistent locus-specific
instability of yellow2-717 and NotchUc-1 in Drosophila melanogaster coincides
with hobo multiplication. Cell and Tissue Biology. Vol 1, No 6, pp. 497-502.
Pleiades Publishing, Ltd. 2007.
15. Sarkar R, Guffei A, Vermolen BJ, Garini Y, Mai S. Alterations of centromere
positions in nuclei of immortalized and malignant mouse lymphocytes. Cytometry
Part A. 71(6):386-92. 2007.
16. Caporali A, Wark L, Vermolen B, Garini Y, Mai S. Telomeric aggregates and endto-end chromosomal fusions require myc boxII. Oncogene 26(10):1398-1406.
2007. Epub 2006 Sep 4.
17. Mai S, Imreh S. Non-random genomic instability: A fact, not an illusion. Semin
Cancer Biol. 17: 1-4. 2007. [Epub ahead of print: Nov 12, 2006]
18. Kuttler F and Mai S. Formation of non-random extrachromosomal elements
duringdevelopment, differentiation and oncogenesis. Semin Cancer Biol. 17: 5664. 2007. [Epub ahead of print: 2006 Oct 26]
19. Intasai N, Mai S, Kasinrerk W, Tayapiwatana C. Binding of multivalent CD147
phage induces apoptosis of U937 cells. Int Immunol. 18(7):1159-69. Epub 2006
Jun 1.
20. Cao L, Kim S, Xiao C, Wang R-H, Coumoul X, Wang X, Li WM, Xu XL, De Soto
JA, Takai H, Mai S, Elledge SJ, Motoyama N, Deng C-X. ATM-chk2-p53 activation
prevents tumorigenesis at an expense of organ homeostasis upon Brca1 deficiency.
The EMBO J. 25(10):2167-77. 2006. Epub 2006 May 4.
21. Mai S and Garini Y. The significance of telomeric aggregates in the interphase
nuclei of tumor cells. Journal Cell Biochem. 97: 904-915. 2006 Jan 11; [Epub
ahead of print]. Article and journal cover.
Invited Seminars and Presentations at Symposia/Meetings
1.
Hodgkin’s lymphoma cells rearrange their genome through breakage-bridge-fusion
cycles. AACR, Denver, 2009. (Amanda Guffei, Hans Knecht, Sabine Mai).
2. Anti-estrogen resistant breast cancer cells differ in their 3-dimensional
chromosomal arrangements from their parental cells. AACR, Denver, 2009
(Johannes von Vopelius-Feldt, Andreea Nistor, Sabine Mai, Sabine HombachKlonisch).
3.
Nuclear architecture in human thyroid carcinoma revealed by three-dimensional
(3D) telomere imaging: New insight into genomic instability and potential
diagnostic application. AACR, Denver, 2009. (Thomas Klonisch, Landon Wark,
Sabine Hombach-Klonisch, Cuong Hoang-Vu, Sabine Mai)
4. Telomere-poor “ghost” nuclei define Reed-Sternberg cells as end-stage cells.
AACR, Denver, 2009 (Sawan B, Lichtenzstejn Z, Lichtenzstejn D, Mai S, Knecht
H.)
5.
S. Mai. c-Myc –dependent genomic instability. University of Mainz, Germany.
April 2008.
6. S. Mai. c-Myc –dependent genomic instability. University of München, Germany.
April 2008.
7. Lacoste S, Wiechec E, Henriksson M, Klein G, Mai S. Genomic instability in
freshly Epstein-Barr Virus (EBV)-infected B cells. AACR, San Diego, April
85
2008.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
86
Harizanova J, Taylor-Kashton C, Mai S. Summary of the quantitative analyses
of the three-dimensional distribution of chromosomes in mouse cells. AACR,
San Diego, April 2008.
Harizanova J, Taylor-Kashton C, Mai S. Quantitative investigations of the
spatial organization of chromosomes in mouse cells. NCIC Meeting, “Making
Connections: A Canadian Cancer Research Conference”, Toronto. 2007.
Louis SF, Henriksson M, Klein G, Mai S. Epstein Barr virus associated
remodeling of three-dimensional telomere signatures precedes chromosomal
instability. NCIC Meeting, “Making Connections: A Canadian Cancer Research
Conference”, Toronto. 2007.
November 2007. Mai S and Knecht H. Alterations in the three-dimensional
organization of the nucleus precede the onset of genomic instability. NCIC
Meeting, “Making Connections: A Canadian Cancer Research Conference”,
Toronto. 2007.
October 2007. Knecht H, Sawan B, Lichtensztejn D, Lemieux B, Wellinger R,
Mai S. 3D Nuclear Organization of Telomeres in Hodgkin and Reed-Sternberg
Cells. Hodgkin’s Lymphoma Conference. Cologne, Germany 2007.
June 2007. The impact of nuclear remodeling by c-Myc. FASEB summer
conference. Nuclear Structure and Cancer. Vermont.
February 2007. c-Myc-dependent genomic instability: pathways to make a
tumor cell. Bellinson Hospital. Tel Aviv. Israel.
February 2007. c-Myc-dependent genomic instability: pathways to make a
tumor cell. Bar Ilan University. Tel Aviv. Israel.
September 2006. Hormonal Carcinogenesis. Montpellier. France.
August/September 2006. Telomeres and Genome Stability. Switzerland.
April 2006. AACR, Washington DC, USA.
•
c-Myc alters the three-dimensional order of telomeres and chromosomes
in the interphase nucleus. Sherif F. Louis, Bart Vermolen, Fabien Kuttler,
Yuval Garini, Sabine Mai. Proc Amer Assoc Cancer Res 2006;47:[4240]
•
The three-dimensional order of telomeres impacts on tumorigenesis.
Andrea Caporali, Landon Wark, Sabine Mai. Proc Amer Assoc Cancer
Res 2006;47:[4985]
•
Three dimensional organization of telomeres in hereditary and nonhereditary breast cancer. Soumya Panigrahi, Sabine Mai, William
Foulkes, Kimberley Kotar, Louis R. Bégin. Proc Amer Assoc Cancer Res
2006;47:[4991]
Grant Panels and Advisory Committees
Genomic Centre for Cancer Research and Diagnosis: User Committee
CIHR Strategic Training Program "Innovative Technologies in Multidisciplinary
Health Research Training" selection committee
CIHR Strategic Training Program "Innovative Technologies in Multidisciplinary
Health Research
NCIC/CCSRI: Panel J Member
Advisory Board Member, Industrial Technology Centre, Virtual Reality Centre
6th Canadian Symposium of Telomeres and Telomerase at The Narrows Lodge,
Lake Manitoba
One area of research in my laboratory is the study of programmed cell death or
apoptosis, a form of cell suicide. As a result of genetic changes, cancer cells have a
reduced or slowed ability to undergo apoptosis which can also make them more resistant
to anti-cancer drug treatment. To better understand programmed cell death, we have
taken a genetic approach. Several mutant cell lines have been isolated that are defective
in apoptosis. This was done by using a specially constructed virus that, after it infects a
cell, can interfere with the genes that control cell death. The underlying genes disrupted
in the mutant cell lines by the virus are now being studied to understand their role in
programmed cell death. By understanding the genetic basis of resistance to cell death,
completely new treatments can be devised.
One gene that that came out of this screen is the Dlc-2 (Deleted in liver cancer two)
tumor suppressor gene. We are studying the role of this gene, and its closely related
paralog Dlc-1, in tumor cell progression and drug response. To carry out these
experiments we have developed conditional knockout mouse models of these genes.
With these mouse models, we are studying the role of the Dlc genes in lung, liver and
breast cancer progression.
Publications Since 2006
1. Hatch,G.M., Y.Gu, F.Y.Xu, J.Cizeau, S.Neumann, J.S.Park, S.Loewen, and
M.R.A.Mowat.
(2008).
RhoGAP
mediates
ceramide
activation
of
phosphatidylglycerolphosphate synthase and drug response in Chinese hamster
ovary cells. FASEB J. 22:269. [Meeting Abstract]
2. Goncalves Dos Santos,S.A., R.Sarkar, J.Harizanova, A.Guffei, M.Mowat, Y.Garini,
and S.Mai. (2008). Centromeres in cell division, evolution, nuclear organization and
disease. J Cell Biochem. 106: 2040-2058
3. Hatch,G.M., Y.Gu, F.Y.Xu, J.Cizeau, S.Neumann, J.S.Park, S.Loewen, and M.R.A.
Mowat. (2007). StARD13 (Dlc-2) RhoGap Mediates Ceramide Activation of
Phosphatidylglycerolphosphate Synthase and Drug Response in Chinese Hamster
Ovary Cells. Mol.Biol.Cell 19:1083-1092.
4. Booy, E.P., Johar, D., Maddika, S., Pirzada, H., Sahib, M.M., Gehrke,I., Loewen, S.,
Louis, S.F., Kadkhoda, K., Mowat, M., and Los, M. (2006) Monoclonal and
Bispecific Antibodies as Novel Therapeutics. Arch. Immunol. Ther. Exp., 54: 1B17
87
Professional Service
Grant Review Committees
National Cancer Institute of Canada, Panel J: Pathology and Tumour Markers 20052008
CIHR Research Advisory Group, U. of Manitoba 2005-present
Department Service
Biochemistry & Medical Genetics
Graduate Affairs Committee, Biochemistry & Medical Genetics 2007-present
Member, PhD Candidacy examination committees, 2005 to 2009
Member, Graduate Student Admissions Committee, 2009-present
Administrative Service - MICB
Executive committee MICB
CIHR Innovative Technologies In Multidisciplinary Health Research Training
Programme selection committee.
Chair, CancerCare MB library committee.
Awards to trainees
Golom Sabbir, (postdoctoral fellow), top poster awards 1. CancerCare Manitoba
Research Day, May, 2009. 2. Canadian Student Health Research Forum, June 2, 2009
88
My overall research focuses on the study of gene expression during human breast
tumorigenesis and breast tumor progression.
Designing therapies slowing down or inhibiting estrogen signalling in breast cells has
already saved thousands of women. Unfortunately, resistance to a specific drug can occur
in some patients and alternative treatments remain needed. It appears that a combination
of drugs, targeting different critical points of estrogen signalling at different times, will
provide a more efficient protection and overcome the potential resistance to a single drug.
The original face of the products of the SRA1 gene consisted of a non-coding functional
RNA (SRA), able to activate estrogen receptors action. We have however demonstrated
that this RNA also leads to the production of a protein (SRAP), which also acts as
modulator of estrogen receptor action. We found that the action of this newly discovered
SRAP is depending upon the receptor ligand, the cell context and the target genes
considered.
The bi-faceted SRA RNA/SRAP system, consisting of a functional RNA and its
corresponding protein, is therefore a newly discovered mechanism used by breast cells to
modulate estrogen action. We hypothesize that characterization of SRA RNA/SRAP
mechanism of action could provide new windows of opportunity to design innovative
therapeutic or preventive strategies to fight breast cancer.
Publications Since 2006
1. Blanchard, A.A., Skliris, G.P., Watson, P.H., Murphy, L.C., Penner, C., Tomes, L.,
Young, T.L., Leygue, E. and Myal, Y. (2009) Claudins 1, 3, and 4 protein expression
in ER negative breast cancer correlates with markers of the basal phenotype.
Virchows Arch, 454, 647-656.
2. Skliris, G.P., Leygue, E., Watson, P.H. and Murphy, L.C. (2008) Estrogen receptor
alpha negative breast cancer patients: estrogen receptor beta as a therapeutic target. J
Steroid Biochem Mol Biol, 109, 1-10.
3. Skliris, G.P., Hube, F., Gheorghiu, I., Mutawe, M.M., Penner, C., Watson, P.H.,
Murphy, L.C., Leygue, E. and Myal, Y. (2008) Expression of small breast epithelial
mucin (SBEM) protein in tissue microarrays (TMAs) of primary invasive breast
cancers. Histopathology, 52, 355-369.
89
4. Leygue, E. (2007) Steroid receptor RNA activator (SRA1): unusual bifaceted gene
products with suspected relevance to breast cancer. Nucl Recept Signal, 5, e006.
5. Blanchard, A., Shiu, R., Booth, S., Sorensen, G., DeCorby, N., Nistor, A., Wong,
P., Leygue, E. and Myal, Y. (2007) Gene expression profiling of early involuting
mammary gland reveals novel genes potentially relevant to human breast cancer.
Front Biosci, 12, 2221-2232.
6. Skliris, G.P., Leygue, E., Curtis-Snell, L., Watson, P.H. and Murphy, L.C. (2006)
Expression of oestrogen receptor-beta in oestrogen receptor-alpha negative human
breast tumours. Br J Cancer, 95, 616-626.
7. Hube, F., Myal, Y., Leygue, E., Rollin, J. and Gruel, Y. (2006) Expression of two
breast-specific molecules in the lung. J Mol Diagn, 8, 390-391.
8. Hube, F., Myal, Y. and Leygue, E. (2006) The promoter competition assay (PCA):
a new approach to identify motifs involved in the transcriptional activity of
reporter genes. Front Biosci, 11, 1577-1584.
9. Hube, F., Guo, J., Chooniedass-Kothari, S., Cooper, C., Hamedani, M.K., Dibrov,
A.A., Blanchard, A.A., Wang, X., Deng, G., Myal, Y. et al. (2006) Alternative
splicing of the first intron of the steroid receptor RNA activator (SRA) participates
in the generation of coding and noncoding RNA isoforms in breast cancer cell
lines. DNA Cell Biol, 25, 418-428.
10. Hube, F., Chooniedass-Kothari, S., Hamedani, M.K., Miksicek, R.J., Leygue, E.
and Myal, Y. (2006) Identification of an octamer-binding site controlling the
activity of the small breast epithelial mucin gene promoter. Front Biosci, 11,
2483-2495.
11. Chooniedass-Kothari, S., Hamedani, M.K., Troup, S., Hube, F. and Leygue, E.
(2006) The steroid receptor RNA activator protein is expressed in breast tumor
tissues. Int J Cancer, 118, 1054-1059.
12. Blanchard, A.A., Watson, P.H., Shiu, R.P., Leygue, E., Nistor, A., Wong, P. and
Myal, Y. (2006) Differential expression of claudin 1, 3, and 4 during normal
mammary gland development in the mouse. DNA Cell Biol, 25, 79-86.
Invited Seminars and Oral presentations at Symposia/Meetings
1. BIT's World Cancer Congress, Nuclear Receptor Symposium, Shanghai, China (2008)
2. BIT's World Cancer Congress, Endocrinology Session, Shanghai, China (2008)
3. Cochin Institute (Paris, France) (2007)
4. INSERM, Montpellier, France (2007)
5. Canadian Breast Cancer Research Alliance, CBCRA meeting in Montreal (2006)
Panels
1. Operating grant competition of the National Cancer Institute of Canada (NCIC)
2. PhD and Post-doctoral Awards, US-Army Medical Research and Materiel Command
(USAMRMC)
90
This laboratory conducts research in the areas of molecular endocrinology and breast
cancer biology. Current research focuses on the molecular mechanisms by which
human breast cancer cells destroy bone.
Publications Since 2006
1. Xu Di, Shiu R, Newsham, IF, Gewirtz DA (2009) Apoptosis, autophagy, and
accelerated senescence in the response of human breast tumor cells to
Adriamycin. Biochem. Pharmacol 77: 1139-1150
2. Xie Y, Yang H, Miller JH, Shih DM, Hicks GG, Xie J, Shiu R (2008) Cells
deficient in oxidative DNA damage repair genes Myh and Ogg1 are sensitive to
oxidants with increased G2/M arrest and multinucleation. Carcinogenesis
29:722-728
3.
Blanchard A, Shiu R, Booth S, Sorensen G, DeCorby N, Deng G, Nistor A,
Wong P, Leygue E & Myal Y. (2007) Gene expression profiling of early
involuting mammary gland identifies novel genes associated with human breast
cancer. Frontiers in Bioscience 12: 2221-2232.
4.
Skliris GP, Lewis A, Emberley E, Peng B, Weebadda WK, Kemp A, Davie JR,
Shiu RP, Watson PH, Murphy LC (2007) Estrogen receptor-beta regulates
psoriasin (S100A7) in human breast cancer. Breast Cancer Res. Treatment
104:75-85
5.
Gerald DeMasters, Xu Di, Irene Newsham, Robert Shiu and David A. Gewirtz
(2006) Potentiation of radiation sensitivity in breast tumor cells by the vitamin
D3 analog, EB 1089 through promotion of autophagy and interference with
proliferative recovery. Mol. Cancer Therap. 5: 2786-2797
6.
Blanchard AA, Watson PH, Shiu RP, Leygue E, Nistor A, Wong P, Myal Y.
(2006) Differential expression of claudin 1, 3, and 4 during normal mammary
gland development in the mouse. DNA Cell Biol 25:79-86
91
External Reviewer
Medical Research Council of Canada, Manitoba Health Research Council, Health
Sciences Center Research Foundation (Winnipeg), Swedish Cancer Foundation, U.S.
National Science Foundation, U.S. Department of Energy, Australian National Health
& Medical Research Council
Scientific Journals
Member, Editorial Board of Endocrinology (U.S.A.)(1984-1988) Reviewer (active) for
U.S. journals: Endocrinology, Molecular Endocrinology, J. Clin. Endocr. Metab.,
Cancer Research, Science, Breast Cancer Research & Treatment, American Journal of
Physiology, Proc. Natl. Acad. Sci. Canadian journal: Mol. Cell Biochem.
Dr. Shui resigned in June of 2009 as a Senior Investigator of MICB
92
Peter is Chief Physician at the BC Cancer Agency Vancouver Island Centre, breast
pathologist, scientist with focus on molecular pathology, and leader in biobanking. In the
latter role he is the director of the BCCA’s Tumor Tissue Repository program (since 2005)
and director of the CIHR Manitoba Breast Tumor Bank (since 1993) and co-leader of local
(VIC-PREDICT program, since 2006), provincial (MSFHR BC BioLibrary, since 2007)
and national (CIHR Canadian Tumor Repository Network, since 2003) biobanking
framework programs and is a member of the executive of the NCIC-CTG Correlative
Sciences and tumor banking committee. Peter is also a senior scientist at the Manitoba
Institute of Cell Biology. His own research program has pioneered molecular approaches
to analysis of human breast tumors and has contributed to the discovery and delineation of
several potential biomarkers and therapeutic targets in breast cancer. These include
delineation of potential relevance of components of the Estrogen Receptor network,
discovery of the S100A7-Jab1 pathway, and definition of CAIX & CAXII as tissue
biomarkers of hypoxia in breast tumors.
Publications Since 2006
1.
Gulisa Turashvili, Steven McKinney, Lisa Martin, Karen A Gelmon, Peter Watson,
Norman Boyd and Samuel Aparicio. Columnar cell lesions, mammographic density
and breast cancer risk. Breast Cancer Research and Treatment. 2008.
2. Wang, J., Barnes, R.O., West, N.R., Olson, M., Chu, J.E., Watson, P.H., Jab1 is a
target of EGFR signalling in ER-alpha negative breast cancer. Breast Cancer
Research Jun 5 10:R51. 2008
3. Yang T, Wall EM, Milne K, Theiss P, Watson PH, Nelson BH. 2007. CD8+ T Cells
Induce Complete Regression of Advanced Ovarian Cancers by an Interleukin (IL)2/IL-15 Dependent Mechanism. Clinical Cancer Research. 13(23):7172-80.
4. Skliris GP, Leygue E, Watson PH, Murphy LC. Estrogen receptor alpha negative
breast cancer patients: Estrogen receptor beta as a therapeutic target. J Steroid
Biochem Mol Biol, Epub 2007 Dec 8.
5. Turashvili G., Hayes M., Gilks B., Watson, P., Aparicio, S. Are columnar cell lesions
the earliest histologically detectable non-obligate precursor of breast cancer?
Virchows Archiv. Manuscript No. VA-08-0062.R1
6.
Wall, E.M., Milne, K., Martin, M.L., Watson, P.H., Theiss, P., Nelson, B.H. 2007.
Spontaneous mammary tumors expressing an epitope-tagged HER2/neu oncogene
show a range of therapeutic responses to adoptively transferred CD4+ and CD8+ T
cells. Cancer Research. Jul 1; 67(13): 6442-6450. PMID: 17616705
93
7.
Skliris GP, Lewis A, Emberley E, Peng B, Weebadda WK, Kemp A, Davie JR, Shiu
RP, Watson PH, Murphy LC. Estrogen receptor beta regulates psoriasin (S100A7) in
human breast cancer. Breast Cancer Research and Treatment, Epub 2006 Sep 29.
Jul;104(1):75-85.2007.
Mandal S, Curtis L, Pind M, Murphy LC, Watson PH.. S100A7 (psoriasin)
influences immune response genes in human breast cancer. Experimental Cell
Research. Aug 15;313(14):3016-25. Epub 2007 Mar 30; 2007
Weitsman GE, Skliris G, Ung K, Peng B, Younes M, Watson PH, Murphy LC.
Assessment of multiple different estrogen receptor-beta antibodies for theirability to
immunoprecipitate under chromatin immunoprecipitation conditions. Breast Cancer
Res Treat. Nov;100(1):23-31 2006
Weitsman GE, Li L, Skliris GP, Davie JR, Ung K, Niu Y, Curtis-Snell L, Tomes L,
Watson PH, Murphy LC. Estrogen receptor-alpha phosphorylated at Ser118 is
present at the promoters of estrogen-regulated genes and is not altered due to HER-2
overexpression. Cancer Research. Oct 15;66(20):10162-70. 2006
Oldford SA, Robb JD, Codner D, Gadag V, Watson PH and Drover S. Tumor cell
expression of HLA-DM associates with a TH1 profile and predicts improved survival
in breast carcinoma patients. International Immunology, Nov;18(11):1591-602.
Epub 2006 Sep 20. 2006
Skliris GP, Leygue E, Curtis-Snell L, Watson PH, Murphy LC. Expression of
oestrogen receptor-beta in oestrogen receptor-alpha negative human breast tumours.
Br J Cancer. 2006 Sep 4;95(5):616-26. Epub Aug 1. 2006
Blanchard AA, Watson PH, Shiu RP, Leygue E, Nistor A, Wong P, Myal Y.
Differential expression of claudin 1, 3, and 4 during normal mammary gland
development in the mouse. DNA Cell Biol. Feb;25(2):79-86. 2006
Nistor A, Watson PH, Pettigrew N, Tabiti K, Dawson A, Myal Y. Real-time PCR
complements immunohistochemistry in the determination of HER-2/neu status in
breast cancer. BMC Clin Pathol. Jan 18;6(1):2 [Epub ahead of print] 2006
Hack TF, Degner LF, Watson P, Sinha L. Do patients benefit from participating in
medical decision making? Longitudinal follow-up of women with breast cancer.
Psychooncology. Jan;15(1):9-19. 2006
Dr. Leigh Murphy and Dr. Peter Watson
94
The Genomic Centre for Cancer Research and Diagnosis (GCCRD) has one project
manager (Dr Rhea Vallente), a full time technician (Landon Wark) and one full time
computer technician (Daniel Lichtenzstejn) to perform training of new personnel, to assist
with imaging and to maintain and/or upgrade the GCCRD equipment, software and data
(back-ups, networking and archiving).
"The GCCRD is overseen by a user committee. It consists of Dr. Sabine Mai (GCCRD
Director), Dr. Jim Davie (GCCRD Co-Director), Drs. James Johnston, Spencer Gibson,
Michael Mowat and Leigh Murphy (MICB Director)."
One of the GCCRD mandates is education. We have been involved in running weekend and
summer workshops with students from the Pembina Trails School Division. 142 high school
students were trained since the program started in 2002, the training was done in basic
plasmid preparation techniques, restriction digestions, gel electrophoresis experiments,
chromosome harvesting techniques, Fluorescent in situ hybridization and imaging. Eighteen
of the students were from our international exchange program that involves high schools in
Germany and Australia. Last year we trained 29 high school students, 7 of them from
Australia. More than 400 high school students have come through since 2000 (tours,
weekend workshops and summer training).
In 2002, we obtained a CIHR Strategic Training Program Grant entitled: “Innovative
Technologies in Multidisciplinary Health Research Training.” This training grant provides
us with $1.8 million over 6 years. Dr. Sabine Mai is the Principal Investigator on this
grant. Co-mentors are from the University of Manitoba, the OCI (Toronto, ON), the NIH
(Bethesda, Maryland, USA), the Karolinska Institute (Stockholm, Sweden), the University
of Rennes (France), and the German Cancer Research Centre (Heidelberg, Germany). The
GCCRD serves as the training base for innovative technologies as outlined in the grant and
on our training website (http://www.itmhrt.ca). Zelda Lichtensztejn coordinates the
workshops and all educational aspects that are part of the Strategic Training Program. We
have held three workshops per year at MICB since implementation of the program. These
are 16 workshops until to date. Participants have come from MICB, the University of
Manitoba, the University of Toronto, the United Kingdom, France, the Netherlands,
Sweden, France, Germany, Brazil, the United States, The Philippines, Denmark,
Switzerland, and Thailand.
95
the year, the GCCRD is involved in tours through the facility.
Lichtenzstejn is involved in organizing tours. On average, 1-3 tour groups per
come through the centre. Tour groups consist of up to 20 individuals. Tours
high school students (e.g. Balmoral Hall, St. John’s Raven’s Court and Kildonan
Collegiate), as well as representatives from industry and politics, and interested
.
Centre has been created as a regional/national facility for research in genomic
and mechanisms of neoplasia. The objectives are focused on research in early
of cancer and novel cancer treatments and on teaching and training of highly
personnel.
Genomic Centre has been designed as a high-technology facility for digital imaging
analysis. The activities have been divided into two separate areas, basic research and
services, to promote a better interaction between different fields of research.
Basic Research support is developed in collaboration with scientific groups from
USA and Europe. The technical services are offered on a fee basis, and they are
focused on fluorescent in situ hybridization, immunohistochemistry and
of biological material. The Centre does not carry out clinical diagnostics,
collaborations with laboratories of clinical genetics are strongly encouraged.
though the workstations are organized independently, they are interconnected by our
server and have internet access. Below follows a description of each system indicating
current available features and applications. The workstations will be modified as
and new software versions are added and this will further increase the current
capabilities of each system.
MetaSystems Group Inc.
Isis software is used for fluorescent in situ hybridization (FISH), multicolor-FISH (Mand comparative genomic hybridization (CGH) for the analysis of chromosomes,
nuclei and tissue sections. Our system allows for the analysis of up to nine
fluorophores for M-FISH. MetaSystems Group Inc. software features fully
image acquisition for M-FISH, automated filter exchange with real-time image
plus automatic and interactive time control for each colour channel.
The In Focus application offers quasi 3-dimensional analysis of FISH-probed and
fluorescent immunostained cells and tissues.
MetaSystems Group Inc. offers a case database for both Isis and Ikaros, and the system can
also perform statistical analysis.
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: fluorescent in situ hybridization (FISH); karyotyping, both fluorescent and
field; multicolor-FISH (M-FISH); comparative genomic hybridization (CGH);
analysis of cells and tissues after FISH or fluorescent immunostaining.
Empix system features fully automated image acquisition for each type of fluorescent
automated filter exchange with live image computer screen plus automatic and
time control for each colour channel. It features joystick motorized stage
as well as fully motorized functions that are completely software driven.
: photography of light microscopy samples (H/E stained samples, Giemsakaryotypes and chromosomes etc.); visualization and quantification of protein, DNA
RNA within the same cell(s); image overlay and analysis; cell morphology studies;
.
Deconvolution (Zeiss)
system features fully automated image acquisition for each type of fluorescent analysis,
filter exchange with live image computer screen plus automatic and interactive
control for each colour channel. It features joystick motorized stage movement as well
fully motorized functions that are completely software driven.
: photography of fluorescent samples for 3D analysis; visualization of protein,
and RNA within the same cell(s); image overlay and analysis; cell morphology studies.
Live Cell Analysis (Zeiss)
system features fully automated image acquisition for each type of fluorescent analysis,
filter exchange with live image computer screen plus automatic and interactive
control for each colour channel. It features joystick motorized stage movement as well
fully motorized functions that are completely software driven.
Zeiss microscope is also equipped with a heated stage and chamber (Bioptechs Inc.),
us to combine cell culture with microscopy and imaging, and other live cell
.
: photography of light microscopy and fluorescent samples (H/E stained,
-stained karyotypes and chromosomes etc.); visualization of protein, DNA and RNA
the same cell(s); image overlay and analysis; cell morphology studies; densitometry;
cell analysis.
Workstation #5 Applied Imaging
: high-resolution photography of cells, tissues, and chromosomes by light
; high-resolution image acquisition and analysis of immunostained cells or
; measurement of relative distance/length and relative fluorescent intensity of
signals in cells or on chromosomes; CGH.
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Workstation #6 SKY (Applied Spectral Imaging Inc.)
Applied Spectral Imaging system works through complementary software applications.
Imaging (SI) version 5.5 software is dedicated to image acquisition and the
2.1.1 version software allows the user to analyze the images acquired in SI 5.5.
Applied Spectral Imaging system features fully automated image acquisition for
analysis of cells and tissues.
: spectral karyotyping (SKY); spectral signatures of cell and tissue; spectral
; spectral imaging.
#7 Laser Chromosome Microdissection
-10 Micro-pipette puller which is used to make micro
-manipulators, and micro-needles for dissecting material.
laser micro-dissection of tissues, cells and chromosomes.
#8 Histology and Pathology and Data Archiving
: At this workstation, pathology samples can be imaged. Also, projection and
slides can be scanned, directly imaged and archived. This capability allows the
to create a database comprising as many as 100,000 slides for future use. This
system is also provided for teaching purposes. It has the capability to image
using bright field, phase contrast, fluorescent and polarized light.
Fluorescent Workstation #10 Scanning Microscope
Applications: Fluorescent in situ hybridization (FISH); karyotyping, both fluorescent and
bright field; multicolor-FISH (M-FISH); comparative genomic hybridization (CGH); FISH
spot counting; ploidy analysis; rare cell detection e.g./ tumour cells; Zeiss Microcom
Cryostat HM560.
Fluorescent Workstation # 11: ApoTome
Equipment and Software:
1. Zeiss AxioImager Z1 microscope
2. Zeiss Axio Cam HRm
3. Zeiss Apotome system
4. Zeon computer with dual monitors
5. AxioVision version 4.4
Applications:
The Apotome allows the fast, high-quality production of optical sections through
fluorochromed biological specimens.
Website
The GCCRD website has been updated and can be viewed at the following URL:
http://www.umanitoba.ca/institutes/manitoba_institute_cell_biology/GCCRD/Index3.htm
98
Manitoba Breast Tumour Bank
Overview
The Manitoba Breast Tumor Bank is a collection of tissue and related clinical data. The Bank
operates within the Department of Pathology of the Winnipeg Regional Health Authority and
University of Manitoba, and CancerCare Manitoba. The Bank was originally established by
the National Cancer Institute of Canada in 1993 with funds from the Canadian Cancer
Society and is now supported by CancerCare Manitoba Foundation in partnership with the
University of Manitoba and the Canadian Institutes of Health Research (CIHR). The Bank
provides an important resource both for breast cancer research at the University of Manitoba
and for researchers across Canada and internationally.
During the assessment of each breast biopsy specimen small tissue samples are taken by
Pathologists to process and examine under a microscope and these samples are then stored as
a ‘clinical archive’. After all diagnosis has been completed the Bank organizes these tissues
and related clinical data into ‘cases’ for both future research and future clinical purposes and
stores these ‘cases’ in CancerCare Manitoba. Researchers can apply to study these cases only
through a review process and if they obtain approval for their research project from an
institutional ethics review board. If approved, researchers are provided with tissue sections
and the related clinical information from a set of typically 100 or more ‘cases’. These cases
are carefully selected from the computer database on the basis of selection criteria such as
size and type of tumor that are relevant to the research question under study. All cases are
distinguished by a Tumor Bank number but are anonymous due to the absence of any tag that
might allow it to be traced to an individual patient. Researchers are charged to cover the
costs of storage and release but no tissue or information is sold. The Bank has supported over
50 research studies on breast cancer across North America and Europe.
The Bank stores three types of information on each case within a secure location in
CancerCare Manitoba. This information relates to the tissue, clinical, and follow-up
information. Tissue information includes the composition of the tissue, the size and type of
tumor. Clinical information includes the patient age, clinical symptoms and the results of
clinical tests such as x-rays. Follow-up information includes the type of treatment after
surgery and the response to this treatment. Information is never released from the Bank with
any label that might allow it to be traced to an individual. Information is only released as part
of a set of anonymized cases, where each case is labeled by an anonymous tumor bank
number and consists of a section of tissue with related information.
99
Update
With the renewal of the Manitoba Breast Tumor bank by CIHR in 2006, came an expanded
mandate to collect from other disease sites. Therefore the most significant news to report
for 2008 is that standard operating protocols for collection and banking of Head and Neck
Cancers and Lung Cancers have been established and we have started to collect Head and
Neck and Lung Cancer specimens.
Operations: Consent. Informed consent continues to be obtained for use of samples and
data for research. Potential clients are first asked by the clinic staff if they are willing and
interested in being approached to participate in a Tissue Bank research study. Those clients
who sign a preliminary invitation to participate form are then contacted by the consent
nurse to discuss and consider participation in the MTB project. This informed consent
process was initiated initially for breast tissue collection in Dec 13th 2004. The total
number of consented subjects for breast as of Dec 2008 is 2,184.
Operations: Supplies and Expenses. During the previous 12 months of full operation
(April 1st to March 31st) in our lab area within CancerCare Manitoba, the MTB supplies
expenses have been $ 53,190.
Operations: Access, Release, and Revenue. We have released breast cases in support of
research studies to 7 local laboratories who have been charged $18,406.10 + $2,242.27(to
bill) for the cost recovery of laboratory materials used in the process of release. We have
also released material to 5 external laboratories (investigators in Newfoundland, Alberta,
Ontario and BC x2) who have been invoiced for a total of $37,696.59 for materials
received. We also have some applications from additional external laboratories that are
currently in different stages of processing (x3 applications under review or approved from
Saskatchewan x1, BC x1 and Manitoba x1; and 3 potential applicants provided with letters
of support, Ontario x1 and Nova Scotia x2).
Operations: Personnel. The overall operation of the MBTB continues to be directed by
Dr. Peter Watson and co-directed by Dr Leigh Murphy. The director and co-director have
been assisted by the MTB coordinator, Michelle Parisien, and the following personnel;
Pathologist Dr. Carla Penner (0.3 FTE, MICB funded), Tissue lab manager Sandra Troup
(CIHR funded), Assistant tissue manager, Andrea Fristensky (1 FTE MICB and CIHR
funded), and Clinical consent manager, Kendra-Ann Seenandan (0.5 FTE, U of M Research
infrastructure grant funded), and data coordinator Kathy Bowler (1 FTE MICB
funded).Operations:
The
MBTB
website
can
be
reviewed
at
http://www.umanitoba.ca/institutes/manitoba_institute_cell_biology/MBTB/Index4.htm.
The Molecular Profiling Unit
The Molecular Profiling Unit contains technology platforms that are used to investigate
gene expression at the RNA and protein levels, in multiple breast tumor biopsy sample using
high through-put systems.
100
The unit contains several Ventana auto-staining machines for high through-put
immunohistochemistry (IHC) and in situ hybridization (ISH) analyses of multi-tissue
sections; an automated Tumor Imaging System which captures and documents high
resolution images of the contents of the tumor sections that have been processed on the
Ventana previously; a Nucleic Acid Workstation for the automated extraction of RNA and
DNA from multiple samples; a DNA microchip reader which allows the measurement of
expression of every gene in the human or mouse genome at the level of RNA in any tissue
sample. So the capability of the unit is to profile multiple tumour samples either at the
level specific gene families through hypothesis driven research, or to more globally profile
at the gene expression level to identify new patterns of gene expression which are
associated with risk of disease, disease outcome and response to treatment. The unit has
made further progress associated with molecular profiling of estrogen receptor isoforms in
human breast cancer, identifying potentially better markers of responsiveness to endocrine
therapies, identifying potential markers of risk of invasive breast cancer. The unit will
cooperate with other platforms within the Breast Cancer Research Centre and MICB
generally, and perform molecular profiling required by the research programs within and
associated with the MICB.
Nygard International Molecular Biology Breast Cancer Research Unit
The proteomics facility in the Nygard International Breast Cancer Research Unit is
equipped with CiphergenProteinChip mass spectrometer, HPLC, FPLC, protein
electrophoresis (1D and 2D) and Imager system to study the molecular biology of cancer,
especially to identify biomarkers of breast cancer and prostate cancer. The Facility is
involved in protein purification and identification activites required in on-going breast
cancer research projects.
Professional Associate (J-M Sun): Dr. Sun manages the facility and supervises the
performance, operation and maintenance of the instruments, provides advice in the use of
mass spectrometry and image methods for the analysis and characterization of protein.
Technician (S Teow): ShumeinTeow is trained to operate and maintain the equipment
within this Proteomics Facility, including the CiphergenProteinChip mass spectrometer,
HPLC, FPLC and protein electrophoresis system. She performs cell and tissue sample
preparation, protein isolation, purification and analysis under the supervision of Dr.
Sun.
Technician (Xuemei Wang): Xuemei Wang performs two dimensional protein
electrophoresis and imager analysis of samples from breast cancer and prostate cancer
cells under the supervision of Dr. Sun. She is also involved in projects involving protein
isolation, electrophoresis and analysis under the supervision of Dr. Leygue in Breast
Cancer Research Program.
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MAMMALIAN FUNCTIONAL
GENOMICS CENTRE
Introduction. The Manitoba Institute of Cell Biology is an international leader and
major innovator in Functional and Cancer Genomics. With the recent completion of
the human genome, the next major hurdle for the Human Genome Project will be to
discover what these genes do. Given that we know there are as many as 5,000 human
diseases with a genetic determinant, this new field of functional genomics will have a
tremendous impact on health care and prevention. Our disease focus is clearly cancer.
The Manitoba Institute of Cell Biology has been leading the field by establishing the
first Mammalian Functional Genomics Centre in Canada. The approach combines the
wealth of sequence information available from the Genome Project with powerful
cutting-edge genetic technologies in mice. The result is a national resource that will
provide over 40,000 genetic "knock-out" mutations in mouse stem cells. Each mouse
stem cell has a single gene missing as well as the capacity to actually form an intact
mouse. Because mice are genetically 95% similar to humans they provide an ideal
experimental model system for human disease. The mice that the Functional
Genomics Centre can generate are 100% genetically identical to their mouse
littermates - except for the one missing gene of interest. As such, any deficiency,
defect or disease that might appear in the mutant mouse will be directly linked to the
function of the single gene in question. The importance of discovering gene function
in the context of the whole animal cannot be said too strongly for this is the context of
disease itself - it cannot be modeled or predicted any other way. In this regard, the
mutant mice themselves will not only provide insights into the genetic basis for the
development of human diseases, but will also provide an experimental model to study
the treatment and potential cures for human disease. On a practical note, development
of the mice themselves initiates a chain of propriety that would be considered in all
future discoveries as a result of the mice.
Programs. The MICB Mammalian Functional Genomics Centre, directed by
Dr. Geoff Hicks, continues to provide international leadership in what is currently
being dubbed as the next Human Genome Project. The centre has established a high
throughput technology for the genome-wide creation of a library of transgenic
knockout mice. Knockout mice are considered to be one of the most powerful
approaches to discovering gene function and can be used to reveal how disease-related
genes, like cancer-causing genes, work. It’s a critical first piece of the puzzle towards
understanding what causes diseases in humans, and more importantly, how medicine
can intervene or prevent the ensuing disease processes.
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Dr. Hicks’ Knockout program aims to generate a knockout mouse for every single
gene in the genome. The mice are freely available to the scientific community at
large, thereby providing this powerful tool directly to the hands of every disease
expert in the world. The impact of this project is considered to be so important that it
has led to a worldwide effort to achieve the mouse resource as soon as possible, the
International Mouse Knockout Project. Major funding for the centre was recently
renewed by CIHR will provide the centre with an additional $2.0 M in operating
funds over four years. Most notably, Dr. Hicks is also the lead investigator for a $23
Million Genome Canada application that will provide funding to support the Canadian
initiatives related to the International Knockout Mouse Project. This Canadian led
initiative is now recognized as one of the cornerstone international programs in
Mammalian Functional Genomics.
The next step in the overall strategy is to generate and functionally analyze knockout
mice. Dr. Hicks has established a leading edge Transgenics program located in both
the MFGC and a state of the art transgenic mouse barrier facility located in the
Faculty of Medicine’s Brodie Building. The later, known as the University of
Manitoba Genetic Modeling of Disease Centre (GMC, Dr. Geoff Hicks is the
Scientific Director), provides both the faculty and the province with a full suite of
transgenic services. GMC services are provided in a cost-recovery fee basis to ensure
all members of the Institute and Faculty can have ready access to this powerful
approach to study disease genes and mouse models of human disease. Services
provided include the generation of mice from ES cells, cryopreservation of ES cells,
germ cells, and the rederivation of mouse models brought into the faculty from around
the world. Dr. Hicks has also established the Canadian Mouse Consortium
(www.MouseCanada.ca). The CMC integrates all the major mouse centres across
Canada and will provide essential transgenic services to any Canadian diseasefocused research program.
Finally, the MFGC also provides additional key service platforms to the Institute.
These include a high throughput DNA sequencing facility, a flow-cytometry facility
and a long term cryogenic cell storage facility. Once again, these are provided to
MICB members as cost-recovery services that significantly reduce the operating costs
of MICB research programs. As these services are used by all member of MICB, the
Institute provides support for the on-going maintenance of the key instruments.
In summary, the MICB Mammalian Functional Genomics Centre is currently a leader
in the field and creating an invaluable genetic resource. The Centre's goal is to develop
this resource to its fullest potential by focusing its efforts on the functional analysis of
genes that are known, or suspected to be, determinants of cancer and human disease.
We are hopeful that the true impact of the project will be to discover experimental
mouse models of human disease that would greatly accelerate the development of
pharmaceutical therapies, or even cures, for human cancer.
For more information, see the website at: http://www.EScells.ca/
103
DNA Sequencing Facility
The MICB DNA Sequencing Facility provides DNA sequencing for more than 45 labs at
the MICB and University of Manitoba. Established and supervised by Dr. Don Dubik
since March of 1998, the facility is self-sufficient and provides sequencing service at less
than half the cost of most other Canadian facilities. The facility contains two sequencers:
a single column ABI 310 and an eight column Beckman CEQ8000. The ABI 310 is the
principle sequencer for the facility while the CEQ8000 is used by Dr. Hicks’ Functional
Genomics Group.
For information about the MICB Sequencing Facility see our website at:
http://www.umanitoba.ca/institutes/manitoba_institute_cell_biology/Sequence/Index2.hm
MICB Equipment Maintenance and Glass-washing Area
Salaries are provided for facility monitors and an equipment manager who oversees the
use and operation of multi-lab equipment totalling well over $10M. Service contracts and
a repair budget are also provided for joint used equipment. A wash-up area and salaries
for two full-time staff are provided.
CLL Tissue Bank
Salaries and supplies for a Chronic Lymphocytic Leukemia (CLL) Tissue Bank are
provided. The purpose of this bank is to facilitate basic scientific research in CLL. This
tissue bank stores CLL samples as well as relevant scientific and clinical information
related to each sample stored. The bank is accessed by MICB senior investigators
interested in CLL research with the expectation of expanding the bank as a national
resource with networks established across Canada with long-term national funding.
Salaries for a technician, research nurse and supplies are provided by the Institute.
Confocal Microscope Facility
An advanced confocal microscope, one of only three in Canada, was purchased by MICB
with the assistance of the Canadian Institutes of Health Research, the Canadian
Foundation for Innovation and the Guardian Angel Benefit, a fundraising committee of
the CancerCare Manitoba Foundation. The microscope is unique because it is capable of
examining the biology and metabolic processes inside cells. With the help of laser light,
it creates optical slices of cancer cells and allows detailed examination of various cell
building blocks, including DNA within the nucleus of the cell.
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Microscope Facility
electron microscope facility allows for the visualization of cellular structures and
of specific proteins within cells. This technology has been utilized clinically for
disorders as well as research projects. The facility has been used by senior
at MICB (Drs. Israels, Gibson and Eisenstat) for their research on primary
cell lines and tissues using transmission electron microscopy. We share a new digital
and image analyser system with the Department of Human Anatomy and Cell
.
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Research Affiliates
Frixos Paraskevas, M.D.
Lorne Brandes, M.D.
Asher Begleiter Ph.D.
Professional Associates
Jian Min Sun, Ph.D.
Genevieve Delcuve, Ph.D.
106
Janice Richman-Eisenstat, M.D.
James Lau, M.D.
Research Nurse
Donna Hewitt
Research Associates
Brenda Kuschak, M.Sc.
Shihua He, Ph.D.
Luke de Lange, Ph.D.
George Skliris, Ph.D.
Elizabeth Henson, M.Sc.
Molly Pind, M.Sc.
Hou Yu Chen, M.D.
Ketan Badiani, Ph.D.
Xiaoxing Yu, M.D.
Shunzen Zhang, M.Sc
Ludger Klewes, Ph.D.
Debbie Tsuyuki, Ph.D.
Don Dubik, Ph.D.
Soma Mandal, Ph.D.
Yongqiang Chen
Post-Doctoral Fellows
Sandrine Lacoste
Elizabeth Mclachlan
Robin Erickson
Babu Sajesh
Ganchimeg Ishdorj
Mohammad Sabbir
Arzu Osturk
Research Fellow
Jayson Stoffman, M.D.
Project Manager
Michelle Parisien
CTR Net
C.E.O. Peter Geary
Systems Developer
Arron Suggit
Consent Nurse
Kendra-Ann Deenandan
Informatician
Rui Sun
Director – Bioinformatics
Songyan Liu
Pathologist
Carla Penner
Technicians
Heather Prieditis
Eileen McMillan-Ward
Mario Fonseca
Michelle Brown
Cheryl Taylor-Kashton
Amanda Guffei
Angela Kemp
Cheryl Peltier
Sumin Lu
Daniel Lichtensztejn
Xuemei Wang
Jennifer Constantini
Landon Wark
Charlton Cooper
Administrative Assistants
Nikki Ryan
Cecile Verrier
Charysse Austria
Cybel de Juan
Amy Johnson
Editorial Assistant
Debbie Regier
Office Assistants
Mary Marko
Sharon Klassen
Visiting Researcher
Beatriz Perez-Cadahia
Senior Health Outcomes Analyst
Zoanne Nugent
Project Manager - GCCRD Program
Rhea Vallente
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Djula Arapovic
Andrea Fristensky
Lisa Salter
Wenyan Xiao
Sandra Troup
Tiffany Hernandez
Yulian Niu
Kanyarat Ung
Laurie Lang
Mohammad Hamedani
Agnes Fresnoza
Suhaila Selamat
Guangping Jiang
Scientific Writer
Darren Manley
Genome Prairie
Reno Pontarollo
Faye Pagdonsolan
Lab Aides
Alice Smith
Maria Simao
Leta Klann
Graduate Students (M.Sc.)
Dilshad Khan
Vanessa Pinto
Meenal Moudgil
Evan Booy
Mehdi Eshraghi
Cordula Buse
Hongmei Zeng
Caroline Shields
Yueqin Zhou
Yi Yan
Lin Lin
Students (Project)
Solmaz Nafez
Jamie Zagozewski
Ayat Mneina
Wenjun Zhu
Student (Resident)
Dave Dawe
Animal Care Technician
Terry Germscheid
Chris Taylor
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Lab Assistant
Charlene Bergen
Information Coordinator
Kathy Bowler
Graduate Students (Ph.D)
Meghan Azad
Shilpa Chooniedass-Kothari
Bojan Drobic
Sara Mohammad-Ali-Beiggi
Qi Zhang
Trung Le
Paula Espino
Ju-Yoon Yoon
Jaganmohan Jangamreddy
Teralee Burton
Francisco Mendoza
Graduate Students (B.S.c.)
Tyler Friesen
Mark Lipson
Sumit Sandu
Johnathan Bush
Students (Research)
Landon Wark
Student (Pre-Masters)
Alexander Graves
Students (Summer 2008-2009)
Sophie Davie
George Deng
Nizihti Woldeab
Charles Ung
Alanna Junaid
Shirley Chang
Shira Lerner
Matthew Frankel
Susanne Klonisch
Zoe Cates
Patrick Murphy
Daniel Vincentt
Volunteer Researchers
Dana Henderson
Andrew Ho
Yaping Wang
Yale Michaels
Holly Hunter
Takafumi Yamaguchi
Patrick Johnston
Jennifer Schacter
Sunjay Lakhi
Eddie Noh
Michael Hsu
Eric Tsang
Tiffany Walker
Allan Rodkins
Juliet Daet
Michael Teichman
Suresh Kumar
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