C. Van Raamsdonk, BSc, MA, PhD
 |
Assistant Professor Email: c.vr@ubc.ca |
Research
Interests:
Cancer cells and cells in developing embryos share two
important characteristics: they rapidly proliferate and they are capable of
migrating extensively. Because of this, it has been suggested that perhaps
cancers are formed when adult cells mistakenly trigger dormant embryonic
programs. In our lab, we are addressing this hypothesis using pigment cells,
called melanocytes. Using classical genetic techniques, we seek to identify new
genes that play a role in melanocyte development, to better understand the
basic processes of cell migration, differentiation, survival and proliferation.
We then study the role of these genes in human melanomas, cancers of
melanocytes, which are increasingly common in Canada.
We model the genetics of pigmentation using mice. We start
with chemically mutagenized mice that have visible defects in pigmentation. We
then use forward genetics to identify the gene that is mutated in each mouse
strain. This type of genetic mapping has a fairly long history. In fact, mouse
geneticists used coat colour mutants to generate the first (rough) map of the
mouse genome. However, our lab has given this approach a new twist, in that we
study mouse mutants with darker or lighter skin colour. We have found that the
genes that specifically regulate mouse skin colour are distinct from those that
also regulate coat colour. The vast majority of melanomas arise from
melanocytes located outside of hair follicles in inter-follicular skin, thus we
predict that the study of mouse skin pigmentation mutants, which have long been
overlooked, will be of particular relevance to melanoma.
So far, we have had promising results. For example, while
studying two dark skinned mouse mutants, Dsk1 and Dsk10, we found hyperactive
mutations in GNAQ, a heterotrimeric G protein alpha subunit. These mutations
increase the size of the melanocyte precursor pool during development. In
collaboration with a dermatopathologist, Dr. Boris Bastian, we sequenced GNAQ
in a variety of human melanomas and found that 46% of uveal melanomas,
malignant melanomas of the pigmented tract of the eye, have a somatic mutation
that renders GNAQ constitutively active. GNAQ is the first oncogene to be found
in uveal melanoma and this discovery provides novel therapeutic targets in the
treatment of this disease.
Mice are a bit unusual in that the skin under the coat is
naturally unpigmentated. Since the currently studied mouse skin pigmentation
mutants do not have defects in this region, there could be a number of genes
specific to trunk skin that we are missing. Therefore, we would like to do a
mutagenesis screen on mice with “humanized” skin. We are investigating the
possibility of using hairless (Hr) mutant mice, as these mice have much less
hair and lightly pigmented trunk skin. We suspect that this is due to the
release of melanocyte stem cells into the epidermis from disintegrating hair
follicles, a hypothesis that we are now testing using reporters of the
melanocyte cell lineage.
Beginning with a phenotype of interest and working backwards
to the responsible gene is a very powerful technique. No a priori information
is needed to begin and the search is completely unbiased. Many times,
unexpected or novel pathways are identified. Once a new pathway is found, it opens a huge door into
understanding the process and creates a firm vantage point from which to make
additional discoveries. At this time, surprisingly little is known about the
regulation and development of melanocytes in the inter-follicular skin. There
are many exciting avenues for research waiting to be explored.
Lab
Members:
Mugdha Deo, PhD student in Medical Genetics
Grace Tharmarajah, PhD student in Medical Genetics
Publications:
Van Raamsdonk, C.D., Crosby, M., Garrido, M., Vemula, S.,
Griewank, K., Wiesner, T., Obenauf, A.C., Wackernagel, W., Green, G., Bouvier,
N., Baimukanova, G., Roy, R., Le, N.T., DeMarini, D.J., Gordon, M.S., Busam,
K., Speicher, M.R., O’Brien, J., and Bastian, B.C. (2010). “Frequent mutations
of GNA11 in uveal melanoma.” Manuscript under review.
Van Raamsdonk, C.D., Barsh, G.S., Wakamatsu, K., and Ito, S.
(2009). “Independent regulation of hair and skin color by two G protein coupled
pathways.” Pigment Cell Melanoma Research 22(6):819-826.
Van Raamsdonk, C.D., Bezrookove, V., Green, G., Bauer, J.,
Gaugler, L., Simpson, E.M., Barsh, G.S. and Bastian, B.C. (2009). “Frequent
somatic mutations of GNAQ in uveal melanoma and blue naevi.” Nature
457(7229):599-602.
Van Raamsdonk, C.D. (2009). “Hereditary hair loss and the
ancient signaling pathways that regulate ectodermal appendage formation.”
Clinical Genetics 76(4): 332-340.
Van Raamsdonk, C.D., Fitch, K.R., H., Hrabe De Angelis, M.,
and Barsh, G.S. (2004). “Effect of G protein mutations on skin color.” Nature
Genetics 36(9), 961-8.
Candille, S.I., Van Raamsdonk, C.D., Chen, C., Kuijper, S.,
Chen, Y., Russ, A., Meijlink, F., and Barsh, G.S. (2004). “Dorsoventral
patterning of the mouse coat by a T-Box gene.” PLOS 2(1), 1-13.
Fitch, K.R., McGowan, K.A., Van Raamsdonk, C.D., Fuchs, H.,
Lee, D., Puech, A., Herault, Y., Threadgill, D.W. (2003). “Genetics of dark
skin in mice.” Genes and Development 17(2):214-228.
Cleary, M.A., Van Raamsdonk, C.D., Levorse, J., Zheng, B.,
Bradley, A., and Tilghman, S.M. (2001). “Disruption of an imprinted gene
cluster by a targeted chromosomal translocation in mice.” Nature Genetics
29(1):78-82.
Van Raamsdonk, C.D. and Tilghman, S.M. (2001). “Optimizing
the detection of nascent transcripts by RNA fluorescence in situ hybridization.” Nucleic Acids Research 29(8):E42-2.
Van Raamsdonk, C.D. and Tilghman, S.M. (2000). “Dosage
requirement and allelic expression of PAX6 during lens placode formation.”
Development 127(24):5439-48.