Download Wellcome Trust Centre For Cell

2012
Wellcome Trust Centre for
Cell-Matrix
Research
Overview
This is the first in a new series of brochures from the Cell-Matrix Centre
focusing on recent discoveries and achievements. Included are descriptions of
some our most exciting research discoveries over the last two years, together
with highlights of public engagement, seminar and conference programmes.
We have world class core facilities that underpin our research and have
included descriptions of how they facilitate our discoveries. Training and
turnover are both part of a dynamic research Centre and at the end we include
recent PhD successes and our leavers.
For the details of research labs, publications,
conference talks, comittees, grants
awarded, etc, please visit our website at
www.wellcome-matrix.org
About cell-matrix research
Mission statement
Cell-matrix research is all about how cells interact with
their local microenvironment. These interactions are
necessary to control both how cells actually behave,
and how organs are made. In the Cell-Matrix Centre, we
are uncovering the molecular events that determine
the way cells and matrix work together. Our discoveries
are illuminating new biological principles about how
multicellular life is organised.
Our scientific mission is to understand how cells make
their ECM microenvironment, and how they integrate
ECM-derived chemical and physical cues in order to build
tissues. By doing so we will discover how changes in
cell-matrix interactions cause major human pathologies,
and we will open new avenues for disease prevention,
diagnosis and therapy. The extracellular matrix (ECM) is the material outside of
cells that provides the three dimensional structure of tissues
and gives organs their solidity. This matrix, comprising a
remarkable 70% of proteins and complex carbohydrates in
the body, binds to cells and is crucial for nearly every aspect
of the way that they behave. For example, it is essential for
cell survival, cell division, cell movements and determining
the exact functions that are carried out by almost all cells
in the body. Both chemical interactions between the matrix
proteins and cells, and mechanical forces that arise within
the ECM, determine cell behaviour, and the matrix also
controls our immune systems.
Because of its central role in biology, defects in the ECM
and the way that it interacts with cells underlie many
of the disorders of mankind. For example, cancer, heart
disease, arthritis, inflammatory disorders, and many
skeletal abnormalities have their origins in defective
cell-matrix interactions. This means that understanding
the basic biological principles by which cells and the
ECM work together to form functional organs is a key
requirement for explaining many of the health problems
in modern society.
The work carried out within the Cell-Matrix Centre focuses
on addressing these essential biological research themes.
By connecting with clinical departments, we ultimately aim
to translate our laboratory discoveries to improve diagnosis
and treat medically important diseases both of western
nations and the developing world. Research directions within the Centre
for Cell-Matrix Research
The research focuses on three specific areas in cell-matrix
biology that we believe will lead to a paradigm shift in our
understanding of Development, Ageing and Chronic Disease.
These are:
i) Cell and tissue microenvironment - How cells create a
three-dimensional ECM, how signals from the matrix
control cell programming and behavior and how altered
ECM organisation & cell-matrix interactions cause
disease.
ii) Mechanobiology of matrix - How the physical properties
of ECM are determined, how they regulate cell
behaviour and the formation of tissues from the nano
through to the macro scale, and how altered tissue
stiffness impacts on pathology.
iii) Matrix immunobiology - How the ECM controls the
immune system during normal physiology and ageing,
and how this is dysregulated in disease.
Charles Streuli
Director
New faces
We are always on the lookout for new recruits and we provide a
fantastically supportive atmosphere with full resources for newly
established research teams. The PIs we have recruited in the last two years
are Pat Caswell, a Wellcome Trust Career Development Fellow, Rachel
Lennon, a Wellcome Trust Intermediate Clinical Fellow and Paul Lu, a
Breakthrough Breast Cancer Research Fellow.
Integrin Trafficking
Integrins are an important family of
cell surface receptors for extracellular
matrices, which act in concert with
many signalling receptors. Our
research addresses the mechanisms
that underlie integrin-mediated
coordination of signals from the
extracellular matrix (ECM) and soluble
growth factors and cytokines in cells
as they migrate and differentiate.
Endocytic trafficking is becoming
Patrick Caswell
recognised as an important regulator
of intracellular signalling events. It
is now clear that integrin trafficking
pathways influence the trafficking
of growth-factor receptors and
their downstream signalling. We
use a variety of cell biology and
biochemistry techniques, with
particular focus on live-cell imaging
and photoactivatable fluorescent
proteins, in 3D-model systems that
more closely mimic the physiological
environment found in vivo to
investigate two major areas:
1 Integrin-mediated trafficking and
signalling in cancer
cell invasion
2 Integrin trafficking in
differentiating epithelial cells
Cell adhesion in the glomerulus
The integrity of the glomerular
filtration barrier is critical for health and
loss of barrier function not only leads to
chronic kidney disease; but it is also an
independent cardiovascular risk factor.
Currently, there are no specific therapies
to restore defective barrier function and
there are significant unmet healthcare
needs. Key genetic discoveries have
highlighted the importance of
glomerular podocytes in maintaining
barrier function and disease-causing
mutations are associated with cellcell junction, focal adhesion and
cytoskeletal regulatory proteins. Whilst
the molecular composition of podocyte
cell-cell junctions is unfolding, there
is less understood about podocyteECM interactions. We are using mass
spectrometry-based proteomics and
imaging to investigate glomerular ECM
in health, ageing and disease. We have
built a catalogue of human glomerular
ECM proteins and have found
Rachel Lennon
differential ECM synthesis between
glomerular cell types. To appreciate
intracellular signalling pathways, we
are investigating podocyte adhesion
complexes to build networks of
interacting proteins. Together,
these approaches will build current
understanding of cell adhesion in the
glomerulus with the aim of identifying
therapeutic strategies to restore
defective barrier function.
Stromal-epithelial interactions
Much like individuals in a society,
cells of an epithelial tissue need to
communicate amongst themselves
and with their environment during
organ formation and homeostasis.
Abnormal cell-cell or cell-environment
communications can lead to failure of
organogenesis in embryos or cancer
formation in adult life. We use the
mouse mammary gland, an organ
highly amenable to experimental
manipulations, as a model system to
understand the basis of epitheliumstroma interactions and how their
deregulation may cause breast cancer.
Our research focuses on three major
themes:
1 What are the roles of stromal
microenvironment in regulating
adult stem cells? Paul Lu
2 How is epithelial polarity
maintained in the breast? 3 What role does receptor tyrosine
kinase (RTK) signalling play in
mammary gland epitheliumstroma interactions? And how is
it regulated? Exciting
recent discoveries
Solving the structure of nature’s elasticity
Clair Baldock
All vertebrates rely on an ECM component called “elastin” to provide their tissues with the
ability to stretch and then return to their original shape.
For example, lungs expand with each
intake of breath and elastically contract
on exhalation, and arteries constantly
expand and contract over the course of a
billion heartbeats. The main component
of elastin is a protein called “tropoelastin”.
It is the co-ordinated assembly of many
tropoelastins into elastin that gives tissues
their stretchy properties. Together with
colleagues from the USA and Australia, we
have solved the structure of tropoelastin,
and found it to be a curved, springlike molecule with a “foot” region to
facilitate attachment to cells. Stretching
and relaxing experiments showed that
tropoelastin had the extraordinary
capacity to extend to 8-times its initial
length. It can then return to its original
shape with no loss of energy, making
it a near-perfect spring. Elastics are
used in applications as diverse as tissue
engineering, clothing and transport.
Understanding how the structure of
tropoelastin creates its exceptional elastic
properties is enabling the development
of synthetic “elastin-like” polymers with
potentially wide-ranging benefits.
Baldock et al 2011 PNAS 108, 4322-7.
Muscle weakness associated with dwarfism - it’s all connected
Pseudoachondroplasia (PSACH) is an autosomal dominant skeletal dysplasia characterised by
short-limbed dwarfism, joint laxity and early onset osteoarthritis. It results exclusively from
mutations in COMP, a pentameric ECM glycoprotein, found in cartilage, synovium, tendon,
ligament and skeletal muscle.
PSACH was for a long time only associated
with cartilage/bone (OA and dwarfism)
and ligament ( joint laxity) disorders.
However, mild PSACH patients are
sometimes referred to neuromuscular
clinics with a suspected diagnosis of a
myopathy due to symptoms of muscle
weakness and fatigue. We have now
analysed a COMP knock-in mouse model
of PSACH, and found that the mutant
mice are physically weaker than the
wild type littermates. The myopathy in
mutant skeletal muscle is specifically
localised to the myotendinous and
perimysial junctions, sites where forces
are conveyed and dispersed between
the muscle and tendon. Our results
suggest that the myopathy suffered
by some PSACH patients is located in
the skeletal muscle but actually stems
from structural and biomechanical
abnormalities in the tendons. This
research will ultimately enable a better
understanding of disease process in PSACH
and other musculoskeletal diseases and
may promote the use of a physiotherapy
approach for disease management.
Pirog et al 2010 Hum Mol Genet. 19: 52-64.
Mike Briggs
New insight into a mechanism for AMD – a major cause of blindness
Tony Day
Age-related Macular Degeneration (AMD) is the major cause of blindness in the western
world. AMD is preceded by the formation of small yellow particles in the macula called
‘drusen’, which are associated with the death of photoreceptor cells and the associated loss
of vision.
Some individuals are genetically predisposed to AMD, where for example the
common Y402H mutation in the gene for
complement factor H (CFH) significantly
increases disease risk. It is thought that
this AMD-associated CFH variant may
not work properly within the eye, but the
exact reason for this was not known. We
found that the disease-associated CFH
variant bound poorly to an area of ECM
in the eye termed the Bruch’s membrane,
which is the location where drusen
accumulate. These CFH-binding sites are
largely composed of glycosaminoglycans
(GAGs), but the different CFH variants have
different specificities for the GAGs present
within the Bruch’s membrane. Indeed, the
impaired ability of AMD-associated CFH to
recognise and bind specific GAGs on the
Bruch’s membrane likely results in the poor
regulation of the innate immune system
on this surface. The resulting chronic local
inflammation damages neighbouring
cells, leading to the formation of drusen.
The research provides a new explanation
for AMD and may allow the development
of new therapeutic strategies for its
treatment.
Clark et al 2010 J. Biol. Chem. 285,
30192-30202.
Turning embryonic stem cells into cells for cartilage repair
The process of embryonic development is one whereby stem cells become progressively
different and give rise to hundreds of cell types that form a multicellular organism.
Stem cell biology has tremendous
medical potential in tissue engineering
and regenerative medicine, and has
the potential to cure connective tissue
diseases. However, a major challenge
is how to direct stem cells to become a
specific cell or tissue type on demand, in
order for them to be clinically useful for
transplant surgery. In collaboration with
Sue Kimber (Manchester) we have now
developed a protocol by which human ES
cells can be programmed to form cartilage
cells, using a well-defined culture media
and a cartilage-specific ECM. This research
takes an important step toward growing
functional cartilage in culture, which
may eventually lead to new treatments
for arthritis and cartilage reconstruction
in sports medicine. In addition, the welldefined conditions whereby cartilage
cells are regenerated should allow a
better understanding of the molecular
underpinnings of cartilage programming.
Oldershaw et al 2010 Nat Biotech. 28,
1187-1194.
Tim Hardingham
ECM sensors, integrin trafficking and wound healing
Martin Humphries
Normal dermis is mainly composed of collagen and stationary fibroblastic cells, but it has
low levels of the pro-migratory ECM protein, fibronectin.
When skin is wounded, plasma and
fibronectin floods into the damaged
tissue. Consequently numerous cell types
move into the wound to rebuild the
dermis. Understanding the details of how
cells respond to changes in the ECM will
help to develop better treatments for
improving tissue repair processes. Our
previous work suggested that a fibronectin
receptor called syndecan-4 might sense
the changes in ECM composition. By using
atomic force microscopy, we found that
syndecan-4 reduces the stickiness of cells.
This is due to a different class of ECM
receptors, integrins, becoming internalised
into the cell, allowing faster receptor
turnover, and increasing cell movement.
We also found that two signalling
molecules, caveolin and RhoG, link
syndecan-4 with integrin internalisation.
As with syndecan-4 and caveolin, deleting
the RhoG gene in mice substantially
reduced the closure of dermal wounds
due to defects in cell movement. Our
work changes the way we think about
syndecan receptors. It suggests that when
syndecan-4 encounters a fibronectin
molecule, this switches on a signalling
pathway that accelerates the turnover
of integrin receptors. This research
explains how cells recognise the change
in ECM composition following injury, and
why they are able to move better in a
fibronectin-rich environment.
Bass et al 2011 Dev Cell. 21, 681-93.
New insights into tendon injury
As a result of surgery or injury, our internal organs may become damaged, with associated
internal bleeding.
As the organ heals, cells move into the
blood clot which over time is replaced
by unwanted and painful fibrous tissue
known as an ‘adhesion’. We have studied
the surface of tendons and discovered
that it is covered by a thin layer of
epithelial cells. These cells are found in
many organs and form a thin cover or
“skin” that protects them from damage
and prevents adhesion to neighbouring
tissues. However when the surface skin
of tendon is damaged, the cells inside the
tendon make the unwanted adhesions.
This discovery changes thinking about
how tendons are made during embryonic
development and maintained in
adulthood, and will eventually lead to new
ways of protecting the tendon epithelium
in older people and in athletes.
Taylor et al 2011 PLoS One 6, e16337.
Karl Kadler
Neuropilin-1 regulates PDGFR signalling in mesenchymal stem cells
Cay Kielty
A major ambition of modern medicine is to repair or regenerate damaged tissue. To achieve
this aim, one of the crucial challenges is the formation of new blood vessels.
Activation of platelet-derived growth
factor receptors (PDGFR) on the surface
of adult stem cells plays a prominent role
in the recruitment and differentiation of
cells that form blood vessels. We have now
demonstrated that another receptor on
the surface of mesenchymal stem cells
(MSCs), called neuropilin-1, is essential
for regulating PDGFR activation. In 3D
cultures of MSCs, neuropilin-1 not only
associated with PDGFR, but the interaction
was required for PDGF-induced migration
and the formation of blood vessel-like
structures. This research enhances our
knowledge of how MSCs can be regulated
by growth factors to control their ability
to form new blood vessels. A thorough
understanding of what regulates a stem
cell to differentiate to a specific cell type is
crucial for the future success of cell-based
tissue regeneration therapies.
Ball et al 2010 Biochem J. 427, 29-40.
Talin’s tail controls cell cycle
Charles Streuli
Integrins have crucial roles in sensing the extracellular matrix environment of cells and
delivering signals to control how they behave.
It was known for a long time that
integrins are essential for cell cycle, but it
was not well understood which integrinbinding proteins are involved. In this
study we have identified an important
role for the adhesion complex protein
called talin in this process. Talin has
received considerable attention because
it is the molecule that activates integrins
to bind ECM proteins, and it does this
via its amino-terminal head domain.
We have now discovered that the other
end of the protein, its carboxy-terminal
tail, has a different function. While talin’s
head activates integrins helping cells
to stick to extracellular matrix proteins,
this new study has revealed that its tail
recruits and activates proteins required
for the proliferation of epithelial cells.
The study helps to explain how integrin
adhesions work, and it provides new
insights into the function of a large
scaffold molecule, which has different
regions for activating integrins, linking
to the cytoskeleton, and delivering
intracellular signals. We also found that
talin has a role in cell cycle regulation
of a metastatic mammary cancer line,
lending credence to the idea that
targeting proteins downstream
of integrins might be valuable in
cancer therapy.
Wang P et al 2011 J. Cell. Biol. 195, 499.
A sticky end for parasitic worms
Dave Thornton
Parasitic worms are a major cause of morbidity and mortality in humans.
With up to a billion people infected with
these worms worldwide, their treatment
is a major medical burden. Parasitic worms
live in the gut, which is protected by a
thick layer of mucus. The mucus barrier
is not just slime, but a complex mixture
of salts, water and large ‘sugar-coated’
proteins called mucins that give mucus its
gel–like properties. Our group has studied
worm infection in mice that cannot make
a particular mucin called Muc5ac. We
discovered that these mice were unable
to expel the worms. Muc5ac turns out
to be ‘toxic’ for the worms, so the mucin
protects animals that are able to make
it in their guts. This research may help to
identify who is and who isn’t susceptible
to parasitic worms, and it may eventually
lead to new treatments for people with
chronic worm infections.
Hasnain et al 2011 J Exp Med. 208,
893-900.
New advances help understand inflammatory bowel disease
Mammals have evolved a complex immune system to fight off infections. This process begins
when dendritic cells present the antigens of these pathogens to T-cells.
The resulting immune response is
tightly regulated to prevent our immune
systems attacking harmless foreign
antigens, such as food molecules and
“friendly” commensal gut bacteria. Special
regulatory T-cells, called Tregs, act as
“brakes” to prevent other T-cells from
attacking these harmless antigens. If this
tolerance brakes down in the intestine,
autoimmunity can lead to inflammatory
bowel disease. An important molecule
which allows the induction of Tregs and
tolerance is TGFβ, which needs to be
activated before it can work. We have now
discovered that a type of gut cell that
makes Tregs, the CD103+ dendritic cell, is
specialised in activating TGFβ. These cells
contain a cell surface receptor protein that
activates TGFβ, called αvβ8 integrin. When
we deleted the gene for αvβ8 integrin,
but only in dendritic cells, the cells could
no longer activate TGFβ. Moreover, these
integrin-deleted cells were unable to
make Tregs. Our work shows that gut
dendritic cells are specialized to activate
latent-TGFβ via the avβ8 integrin, and
that this activation process is essential for
their ability to produce Tregs and immune
tolerance. This research may help to
identify new treatments for inflammatory
bowel disease.
Worthington et al 2011 Gastroenterology,
141, 1802-12.
Mark Travis
Seminars
There are two very active, weekly seminar programmes within the Centre. One seminar series gives every PI, postdoc and PhD student
the opportunity to present their research stories to a wide audience. In the other programme, we invite cell-matrix researchers from
around the world to visit the Centre. Here are our visiting speakers in 2010 and 2011.
Elena Aikawa, Brigham and Women’s Hospital,
Harvard Institute of Medicine, USA, Pathologic matrix
calcification: Insights from molecular imaging
Benny Geiger, Weizmann Institute of Science,
Israel, The functional nano-architecture of integrin
adhesions
Anna Akhmanova, Utrecht University, Holland,
Friends at the ends: a dynamic protein network
controls the fate of microtubule tips
Darren Gilmour, European Molecular Biology
Laboratory, Heidelberg, Germany, Dissecting the
role of chemotactic and contact-based guidance
mechanisms during tissue migration in vivo
Kurt Anderson, The Beatson Institute for Cancer
Research, Glasgow, Imaging the molecular dynamics
of metastasis
Albert Basson, King’s College London, FGF signalling
and cerebellar morphogenesis - why signal intensity
matter
Tony Green, Cambridge Institute for Medical
Research, Cambridge, Myeloproliferative neoplasms –
JAK2 signaling and stem cell subversion
Peter Holland, University of Oxford, Homeobox genes,
genomes and animal evolution
Catherina Becker, University of Edinburgh, Controlling
the differentiation and regeneration of motor neurons
Philip Ingham, A*STAR, Singapore, Origins,
mechanisms and functions of Hedgehog signaling
Cord Brakebusch, University of Copenhagen,
Denmark, Rac1 function in skin tumor
Andrew Jarman, University of Edinburgh, Regulation
of neurogenesis in Drosophila: linking cell type
specification to cellular differentiation
Nick Brindle, University of Leicester, Signalling
mechanisms and designer molecules to control blood
vessel formation, regression and function
James Briscoe, MRC National Institute of Medical
Research, London, The gene regulatory logic for
reading the sonic hedgehog gradient in the vertebrate
neural tube
Jeremy Brockes, University College London,
Mechanisms underlying limb regeneration in an adult
vertebrate
Alan Colman, A*STAR, Singapore, Use of human
induced pluripotent stem cells (iPSC ) to model a
human premature aging disease
Maria Dolores Martin Bermudo, Universidad Pablo
de Olavide, Seville, Spain, Mechanisms regulating
collective cell migration
Rosanna Forteza, University of Miami, USA,
Regulation of protease activity and cell signaling by
ECM in the airways
Steffen Jung, Weizmann Institute of Science, Israel,
Probing origins and functions of mononuclear
phagocytes
Carlo Knupp, Cardiff University, Three-dimensional
electron tomography throws new light on the
structure of the cornea
Bjorn Olsen, Harvard School of Dental Medicine,
Boston, USA, Mechanisms for integration of
mechanical and chemical signals during skeletal
development and growth
Jennifer Potts, University of York, Structure and
interactions of surface proteins from pathogenic
bacteria
Olivier Pourquie, University of Strasbourg, France,
Patterning the vertebrate axis
Ralf Richter, CIC biomaGUNE, San Sebastian, Spain,
Structure/function inter-relationships of hyaluronan
matrices and their interaction with cell surface
receptors – insights from well-defined model systems
Liz Robertson, University of Oxford, Genetic
regulation of cell fate decisions in the early mouse
embry
Stefan Schulte-Merker, Hubrecht Institute, Utrecht,
Holland, Genetic analysis of vertebrate organ
formation – zebrafish lymphangiogenesi
Robert Steadman, Cardiff University, Controlling cell
fate in fibrosis: the role of hyaluronan
Claudio Stern, University College London, Making a
brain: a molecular dissection of neural induction
Rebecca Marlow, King’s College London, SLIT/ROBO
Signaling in Mammary Epithelium and Endothelium
Nic Tapon, London Research Institute, Control of tissue
growth by the Hippo signalling pathway in Drosophila
Roberto Mayor, University College London, Migration
of neural crest cells: a balance between repulsion and
attraction
Bernhard Wehrle-Haller, University of Geneva,
Switzerland, Mechanisms of integrin-dependent
adhesion and migration
Tony Ng, King’s College London, An integration of
optical proteomics and mathematical approaches
to define pathways and make predictions for cancer
patients
Stephen Weiss, Michigan, Transcriptional Repressors,
Epithelial-Mesenchymal Cell Transitions and the
Regulation of the Tissue-Invasive Phenotype
Kate Nobes, University of Bristol, Contact inhibition of
locomotion and tumour cell invasion
Matthew Freeman, MRC Laboratory of Molecular
Biology, Cambridge, Intramembrane proteolysis by
rhomboids in signalling and development
Peter O’Hare, Imperial College London,
Transmembrane transcription factors: integrating
the ECM, secretion, ER signaling and adaptive nuclear
responses
Jenny Gallop, University of Cambridge, Understanding
cell shape: reconstitutions of actin polymerisation at
the membrane-cytosol interface
Geraldine O’Neill, The Children’s Hospital at
Westmead, University of Sydney, Australia, Switching
off mesenchymal invasion
Michael White, University of Liverpool, Systems
Microscopy
Steve Wilson, University College London, Breaking
symmetry in the brain: from genes to circuits
Will Wood, University of Bath, Macrophage migration
and chemotaxis in the Drosophilia embryo
Roy Zent, Vanderbilt Medical Center, Nashville, USA,
How do integrins regulate polarized epithelial cells?
The Cell-Matrix Centre has established a conference programme called ‘Get Connected!’
designed to provide a forum for young scientists to present their research stories to an
international audience. Amogst the large number of talks by postdocs and postgrads,
there are presentations from international stars in the field; almost everyone in the
audience (around 100) gets a chance to present talks or posters and there are prizes for
the best! The conferences are organised by PhD students and postdocs in the Centre,
and cover a broad range of cell-matrix research topics. Here are the highlights of the
2010 and 2011 meetings
Conferences
Get Connected 2010
Get Connected 2011
Organisers:
Organisers:
Luke Bonser (Thornton lab), Doug Dyer
(Day lab), Louise Kung (Boot-Handford lab),
Chloe Yeung (Kadler lab)
Gareth Hyde (Canfield lab), Helen Troilo
(Baldock lab)
Keynote speakers
Keynote speakers
Clair Baldock, University of Manchester
Paola Defilippi, University of Turin
Elisabetta Dejana, European Institute
of Oncology, Milan
Paul Martin, University of Bristol
Ulrike Mayer, University of East Anglia
Jim Norman, Beatson Institute, Glasgow
Erik Sahai, London Research Institute
Martin Schwartz, University of Virginia
David Critchley, University of Leicester
Mary Frame, University of Edinburgh
Johanna Ivaska, University of Turku
Cay Kielty, University of Manchester
Sussan Nourshargh, Queen Mary University,
London
Thomas Pap, University of Muenster
Helen Skaer, University of Cambridge
Arnoud Sonnenberg, The Netherlands Cancer
Institute
Session Topics on ECM and adhesion in:
Session Topics on ECM and adhesion in:
Development
Immunology
Cancer
Cell Migrations
The Future of ECM Research
Structure, Assembly and Remodelling of ECM
Signalling via Adhesions
Tissue Repair and Wound Healing
Inflammation and the vasculature
Disease
Developmental biology
Cell signalling
The cytoskeleton
The stem cell niche
Cancer
“I thought scientists were strange people but
they’re actually really normal.”
“It was fun sticking everything together
and experimenting.”
Public
Engagement
Public engagement is a key activity within the Cell-Matrix Centre and
almost all PIs and staff are involved with various events throughout the
year. We have perfected a wide range of unique activities to engage with
schoolchildren from Manchester and the North West, to inspire them to
study science and to teach them about cell-matrix biology.
Here are some examples of what we do.
“I thought the whole day was really excellent.
Working with PhD students on areas set within real
research activities was an absolutely excellent way
to turn students onto science as a career option.
I really believe the students will have gained real
knowledge and enthusiasm from this.”
Wellcome to the Matrix
The A-level study day topics are:
‘Wellcome to the Matrix’ was established
in 2007 and runs every year. This event
affords 14-15 year olds the opportunity
to work with current researchers, from
PhD students to Principal Investigators,
exploring the laboratories, and designing,
creating and presenting models based on
the current research within the Centre.
‘Genes to Phenotypes’ is based on the
Centre’s internationally-recognised
research into short-limbed dwarfism.
A-Level study days
Through collaboration with The
Manchester Museum, the Centre hosts
three different “Engage with the Experts”
study days for A-Level students. These
involve round table study, question
and feedback sessions, together with
practical activities. They are all outside
of the normal school curriculum and are
designed to excite 17-18 year olds about
contemporary research.
“(The scientists)
were funnier than
I expected and
weren’t boring
old professors.”
Feedback: everyone had a better
understanding of science: 78% said they
were more likely to continue studying
science as a result of their experience.
‘A Breath of Fresh Air’ highlights the
Centre’s research into various lung
diseases, and explores the issues behind
research funding.
‘The Rogue Cell’ covers the Centre’s work
into the hallmarks of cancer and discusses
the development of targeted therapies.
Body Experience and Science
Spectacular
The Centre made a major contribution
to these events, which are part of the
National Science and Engineering Week
and the Manchester Science Festival.
Children, parents and grandparents flock
to the event and have the opportunity to
look into the workings of many different
body organs. Centre PIs and students
demonstrate our research into lung
diseases, the heart and blood vessels,
kidneys, eye, tendons and breast biology.
In October 2011, our Scientific Advisory Board
visited the Centre for two days. They worked
tirelessly over that time, talking to PIs and staff,
hearing presentations, reading posters and
appraising the Centre. Their visit was highly
successful and has helped the Centre to develop
new research strategy for the future.
International Scientific
Advisory Board
Our ISAB team are:
Clare Isacke, Chair of the Board
Interim Director of the Breakthrough
Breast Cancer Research Centre
London
Chris Chen
Skirkanich Professor of Innovation
in Bioengineering
University of Pennsylvania,
Philadelphia
David Critchley
Professor of Biochemistry
University of Leicester
Rick Horwitz
Professor of Cell Biology
UVa School of Medicine, Charlottesville
Bjorn Olsen
Hersey Professor of Cell Biology,
Harvard Medical School, Boston
Core Facilities
Many of the advances made within the Cell-Matrix Centre are underpinned by analytical research facilities that allow its researchers to
probe cells and tissues in innovative ways. Highly experienced staff maintain and continually upgrade the equipment, and they work
closely with Centre members to produce innovative and exciting research. We also have access to other dedicated core facilities within
The Biomolecular Analysis Core Facility
The Biomolecular Analysis Facility is
a state-of-the-art resource for the
biophysical characterisation of molecular
hydrodynamics, solution structures and
molecular interactions. The facility is
run by Tom Jowitt and Marj Howard,
and its equipment is housed in purpose
built facilities with all the necessary
bench space, degassers, centrifuges,
spectrophotometers, and the majority
of chemicals that are required to run
experiments. We also provide data back-up
and workstations for data analysis.
We are one of the largest single facilities
of its type with specialist knowledge on
low resolution structure determination
of multi-domain molecules using
hydrodynamics. We also have expertise
on development of nano-biotechnological
surfaces for the investigation of
protein-protein interactions, biological
membranes, and small molecule
associations; and in the investigation of
protein dynamics and complex assembly.
We work closely with members of the
Centre and provide advice, training and
data interpretation to ensure that the
projects are fully supported with the most
appropriate methodology, instrumentation
and strategy.
The Electron Microscope Facility
The Electron Microscope Facility provides
experienced staff who work with the
researchers in the Cell-Matrix Centre to
obtain high resolution 2D and 3D images
of cells and the extracellular matrix. The
facility houses three transmission electron
microscopes and an environmental
scanning electron microscope. We also
have equipment for preparing samples
for cryo-electron microscopy, which can
be visualised on our 3300kV G2 Polara.
A recent acquisition is the Gatan 3view
Tom Jowitt
machine, which allows us to easily
generate serial section reconstructions
through significant volumes of tissues and
constructs.
The facility also has expertise in single
particle reconstruction, offering insight
into protein folding without the need for
crystallisation; and electron tomography,
providing high resolution reconstruction of
a tissue samples.
Toby Starborg
the Faculty of Life Sciences, ranging from histology and atomic force microscopy, to macromolecular crystallography, deep sequencing
and bioinformatics. The four core facilities on these pages are largely funded by the Wellcome Trust and many of their staff are CellMatrix Centre members.For information about our core facilities, please see http://www.ls.manchester.ac.uk/research/facilities/
Light Microscopy
The Bioimaging Facility provides over
20 microscope systems that range from
confocal fluorescent microscopes for
imaging fixed cells and tissue sections,
through to live cell multiphoton systems
and two spinning disk microscopes
allowing the user to image complex three
dimensional events over many hours or
even days. We also have robotic machines
for automated data collection, and laser
micro dissection apparatus. The facility
is run by Peter March and has 3 full time
members of staff.
Peter March
The facility provides both training and
support for the users. A particular focus is
in helping with the design, imaging and
analysis of experiments. This provides
a feedback loop to ensure that the
researchers are using the best microscope
systems for their experiments, which in
turn helps to push the research forwards.
Mass Spectrometry and Proteomics
The Bio-MS Facility is one of the largest
facilities of its type in the UK, containing 8
mass spectrometers and a comprehensive
selection of sample preparation
technologies including electrophoretic
and chromatographic techniques. It
is run by an experienced team of four
analytical staff and one informatition
and is led by David Knight. Investment
in the facility is continuous, with the
latest addition being the Orbitrap Elite
mass spectrometer providing the highest
performance currently available. The
facility also has an informatics room, with
a complementary suite of software for
data analysis and interpretation, as well
as resources for user training. Our primary
role is the identification, characterisation
and quantification of proteins and we also
support the profiling and quantification of
metabolites. Our main focus is the quality
of the results produced and, as well as
providing established methodologies,
we are also involved in developing new
methods in areas such as high resolution
separations, characterising modifications,
and absolute protein quantification.
The facility is more than a collection of
instruments and our aim is to provide the
highest level of support the researchers
who use the facility. As such we support
all aspects of the research process from
project specific advice on experimental
design and sample preparation, to
performing the analyses and aid in data
interpretation.
David Knight
PhDs
We have a dynamic programme for PhD students with a 100% record
in successful training. Most students subsequently develop flourishing
careers in research labs around the world, in biotech, or in science
education or writing. Here are the thesis titles of PhD degrees awarded to
Centre members in 2010 and 2011.
2010
Hellyeh Hamidi
The role of differential phosphorylation of
syndecan-4 in cell migration
Sumaira Hasnain
The mucus barrier: immune defence
against gastrointestinal nematodes
Alexa Jeanes
The role of beta1 integrins in the control of
mammary epithelial cell proliferation
Amanda McGovern
The role of fibulin-5 interactions in elastic
fibre assembly
Matthew Stroud
Functional Characterisation of a Novel
Microtubule-Actin Interacting Protein,
GAS2-like 3
Jennifer Veevers
Mesenchymal stromal cell migration is
regulated by fibronectin through integrinmediated activation of PDGFR-β
Jemima Whyte
Density dependent differentiation of
mesenchymal stem cells to endothelial
cells
2011
Stephanie Jobling
The Notch and Edar signalling pathways
in mammary gland development and
breast cancer
Asia Klementowicz
Investigating regulation of immune
responses during trichuris muris infection
Louise Kung
Investigating the role of endoplasmic
reticulum stress in chondrodysplasias
Ewa Mularczyk
Understanding molecular pathology of
chondrodysplasias: the role of ER stress
Christopher Bayley
Growth factor interactions with plateletderived growth factor receptor alpha
Tanja Torbica
Characterisation of the role of collagen
XXVII in mouse embryonic lung
development
Leavers
It is always sad to say farewell to our staff members who have become
colleagues and friends over the years. Many have moved to take up
fantastic positions around the globe.
Richard Kammerer was a Wellcome Trust
Senior Research Fellow studying protein
structure for 10 years within the Centre,
and departed in 2010 to establish a new
laboratory in the Paul Scherrer Institut,
Switzerland
Adrian Shuttleworth was a founding
member of the Centre and a Faculty
member for 42 years, who made big
advances in understanding matrix
organisation, including his work on ECM
microfibrils. We wish him well in his
retirement
Tariq Ali (Day lab):
Principle Investigator of Protein
Technologies Ltd, Manchester
Mark Bass (Humphries lab):
Wellcome Trust Career Development
Fellow in the School of Biochemistry in
the University of Bristol
Sumaira Hasnain (Thornton lab):
Postdoctoral research officer at Mater
Medical Research Institute, Brisbane
Alexa Jeanes (Streuli lab):
Lead Educator at the Manchester Museum
Stephanie Jobling (Brennan lab):
Researcher at Blueprint Partnership,
Manchester
Asia Klementowicz (Travis lab):
Postdoc in University of California,
San Francisco
Elizabeth Laird neé Canty (Kadler lab):
Lecturer in Orthopaedic Biology, University
of Liverpool
Ben McDermott (Boot-Handford lab):
Postdoctoral researcher at the
Comparative Musculoskeletal Sciences
Research Group, University of Liverpool
Rachel Oldershaw (Hardingham lab):
Research Fellow, Institute of Cellular
Medicine, Newcastle University
Tom Owens (Gilmore lab):
Postdoc at the University of Sydney
Richard Kammerer
Helen Rajpar (Boot-Handford lab):
Senior scientist, Heritable Disorders
Branch, National Institute of Child
Health and Human Development,
Bethesda, Maryland
Matthew Stroud (Ballestrem lab):
Postdoc at the University of California
San Diego
Jennifer Lowe neé Veevers (Kielty lab):
Post-doctoral researcher, Department of
Medicine at the University of California
San Diego
Richard Berry (Baldock lab):
NHMRC Fellow, Department of
Biochemistry and Molecular Biology,
Monash University
Adrian Shuttleworth
Cell-Matrix Centre PIs:
Research topics & contact details
Charles Streuli MA PhD
Director
Integrins in breast biology
[email protected]
Tony Day MA DPhil
Professor
Inflammation and innate immunity
[email protected]
Dave Thornton BSc PhD
Professor
Mucus glycobiology
[email protected]
Clair Baldock BSc, PhD
Senior Lecturer
Matrix protein structure
[email protected]
Andrew Gilmore BA PhD
Senior Lecturer
Anoikis
[email protected]
Mark Travis BSc PhD
RCUK Fellow
Integrin immunobiology
[email protected]
Christoph Ballestrem PhD
Lecturer
Cell adhesion
[email protected]
Tim Hardingham BSc PhD DSc
Emeritus Professor
Cartilage diseases
[email protected]
Gillian Wallis BSc PhD
Professor
Osteoarthritis genetics
[email protected]
Ray Boot-Handford BSc PhD
Professor
Cartilage, dwarfism & osteoarthritis
[email protected]
Martin Humphries BSc PhD FMedSci
Professor
Integrin proteomics
[email protected]
Claudia Wellbrock habil PhD
Reader
Melanoma skin cancer
[email protected]
Keith Brennan BA MA PhD
Senior Lecturer
Developmental mechanisms of breast cancer
[email protected]
Karl Kadler BSc PhD
Professor
Collagen fibrils
[email protected]
Mike Briggs BSc PhD
Wellcome Trust Senior Research Fellow
Skeleteal dysplasias
[email protected]
Cay Kielty BSc PhD FMedSci
Professor
ECM assembly
[email protected]
Ann Canfield BSc PhD
Professor
Vascular calcification
[email protected]
Rachel Lennon BMedSci BMBS PhD MRCP
Wellcome Trust Intermediate Clinical Fellow/
Consultant Pediatric Nephrologist
Cell adhesion in the glomerulus
[email protected]
Patrick Caswell MSc PhD
Wellcome Trust Career Development Fellow
Integrin trafficking
[email protected]
General enquiries to
Anna Fildes +44 161 275 5072
Paul Lu PhD
Breakthrough Breast Cancer Fellow
Stromal-epithelial interactions
[email protected]
Support Staff
Ceri Harrop PhD Public Engagement Programme Manager
[email protected]
Tom Jowitt PhD
Biomolecular Analysis Core Facility
[email protected]
David Knight PhD
Mass Spectrometry Core Facility
[email protected]
Toby Starborg PhD
Electron Microscopy Core Facility
[email protected]