2010 Annual Report - Institute for Molecular Bioscience - University ...

imb annual report 2010
38
BRANDON WAINWRIGHT
TISSUE REPAIR AND CANCER
USING GENOMIC APPROACHES,
our group mapped and isolated the gene
for the heritable cancer disorder, naevoid
basal cell carcinoma syndrome (NBCCS).
The patched gene, discovered from our
studies on NBCCS, has defined a signalling
pathway known as the “hedgehog
pathway”, which appears to be mutated
or perturbed in a wide range of tumour
types, including lung, gastro-intestinal, skin,
pancreatic, prostate, brain and ovarian
cancer. This has led us to focus on the
role of hedgehog signalling, not only in
cancer but also on the regulation of stem
cell compartments. Increasingly it appears
that in some tumour types there are cells
known as “cancer stem cells” which reside
within the tumour and are responsible for
the overall phenotype. Currently such cells
can be partially defined functionally but
their molecular signature remains elusive.
We believe that the patched/hedgehog
pathway defines many of the characteristics
of such stem cells and is a powerful starting
point for understanding tumour biology and
the development of new therapeutics.
Given that cancer represents a state of
unregulated cell growth, it is likely that
the pathways that lead to cancer are
also involved in the normal process of
tissue growth and repair. Several of our
studies are particularly directed at the role
of the hedgehog (and other pathways)
in repair and regeneration. The two
most common cancer types in NBCCS
patients are basal cell carcinoma of the
Above and below: Loss of patched leads
directly to skin tumours.
skin and medulloblastoma, a common
brain tumour occurring predominantly in
children. In the example of both tumour
types we are examining how activation
of the hedgehog pathway causes the
tumour, and defining the cell of origin of the
tumour using a combination of molecular
genetics and cell biology. We are also
defining the interaction of the hedgehog
pathway with other genetic pathways,
such as Notch signalling, in order to
understand the normal development of
the skin and the cerebellum, but also what
therapeutic strategies might be useful to
treat the tumours. In addition to studying
known pathways, we are seeking new
interactions through genomic approaches
to discovering new genes and pathways
in model systems such as mice and
zebrafish. The IMB has a well-developed
drug discovery platform and we are
using our knowledge of the biology of
these tumours to look for potential new
therapeutics.
As part of our experimental approach
our laboratory makes extensive use of
transgenic and knockout mice. However
at all points we refer back to the human
diseases under study and have major
activities based around mutation analysis,
transcriptomics and proteomics of human
material, integrating the data from all
systems.
As a result of these studies we have a
particular interest in the interface between
developmental cell biology and human
genetics, and in therapeutic interventions
such as gene or cell therapies.
RESEARCH PROJECTS
• Controlling neuronal stem cells and
CNS by the patched/hedgehog
pathway
• Investigating the molecular basis of
primary brain tumours
• Controlling the stem cell niche in
mammalian epidermis and skin cancer
• Discovery of new genes capable of
suppressing tumour growth
• The role of microRNAs in brain tumour
development
KEY PUBLICATIONS
The International Cancer Genome
Consortium (Wainwright, B.J. listed
as member of initial scientific planning
committee) (2010). International network
of cancer genome projects. Nature 464:
993-998.
Thomas, W.D., Chen, J., Gao, Y.R.,
Cheung, B., Koach, J., Sekyere,
E., Norris, M.D., Haber, M., Ellis, T.,
Wainwright, B., and Marshall, G.M.
(2009). Patched1 deletion increases
N-Myc protein stability as a mechanism
of medulloblastoma initiation and
progression. Oncogene 28: 1605-1615.
Yang, Z.J., Ellis, T., Markant, S.L., Read,
T.A., Kessler, J.D., Bourboulas, M., Schüller,
U., Machold, R., Fishell, G., Rowitch,
D.H., Wainwright, B.J., and Wechsler-
Reya, R.J. (2008). Medulloblastoma can
be initiated by deletion of Patched in
lineage-restricted progenitors or stem
cells. Cancer Cell 14: 135-145.
Adolphe, C., Hetherington, R., Ellis, T.,
and Wainwright, B. (2006). Patched1
functions as a gatekeeper by promoting
cell cycle progression. Cancer Research
66: 2081-2088.
LAB MEMBERS
Research Officers: Dr Richa Dave, Dr
Rehan Villani, Dr Christelle Adolphe, Dr
Jonathan Robson, Dr Elaine Julian
Research Assistant: Melissa Bourboulas
PhD Students: Uda Ho, Lena Constantin,
Rhonda Kan, Peter Yee
Undergraduate Students: Eriza
Secondes, Paul Joosa, Stephanie Kamp,
Chun Tatt Lim
Visitors: Luis Milla