Our lab investigates pigment cell biology and melanoma, which is a cancer of pigment cells. Melanoma accounts for only 1% of skin cancers, but it causes a majority of skin cancer deaths. It is also the most common ocular cancer. Rates of melanoma have been rising rapidly. Our lab studies this problem mostly in mice, forcing them to develop melanoma through genetic manipulation of oncogenes and tumor suppressors. We are also finding intriguing connections between how pigment cells (called melanocytes) form in the embryo and the types of melanoma these cells give rise to later in life. Although melanoma is the most pressing concern, we are also curious about other pigmentary abnormalities, such as freckling and skin hypo-pigmentation. More specific information about our research can be found below!
1. Melanocyte Diversity
There are over 100 different mouse mutants with hair color defects. Using forward genetics, a large fraction of these mutants have been successfully cloned, identifying genes that play a role in melanocyte development, pigment production and maintenance of stem cell populations. However, studies of melanocytes residing in the skin of mice are still largely lacking. This area of research could be very informative, because many human melanomas arise in a pre-existing nevus in the skin, not from a follicular melanocyte. We have used forward genetics to analyze mouse mutants that have dark skin, without any changes to their hair colour. To our surprise, none of the dark skin mutations mapped to a known hair color locus. Therefore, the genes that regulate skin color are independent and novel. Our further studies in mice support the hypothesis that melanocytes are regulated differentially depending upon their location in the body, which could contribute to the specificity of oncogenic mutations in different melanoma subtypes.
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Fitch, K. R., Mcgowan, K. A., Van Raamsdonk, C. D., Fuchs, H., Lee, D., Puech, A., Herault, Y., Threadgill, D. W., Hrabe De Angelis, M., and Barsh, G. S. (2003). Genetics of dark skin in mice. Gene and Development 17, 214-28.
Van Raamsdonk, C. D., Fitch, K. R., Fuchs, H., De Angelis, M. H., and Barsh, G. S. (2004). Effects of G- protein mutations on skin color. Nature Genetics 36,
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
Pigment Cell and Melanoma Research 22, 819-26.
2. The G proteins, GNAQ & GNA11, are melanoma onocogenes
This project began by using forward genetics to identify the heterotrimeric G proteins alpha subunits, Gnaq and Gna11, as critical regulators of skin colour and melanocyte development in mice. A large scale sequencing project of a variety melanoma subtypes then revealed that GNAQ and GNA11 are oncogenes mutated in the majority of human uveal melanomas, a type of melanoma that develops in the eye. We engineered the first mouse model for uveal melanoma by the conditional expression of the oncogenic version of GNAQ in melanocytes. Excitingly, this model mimics all known effects of GNAQ mutations in humans, providing a way to test potential therapeutics for uveal melanoma, a rare, but deadly disease. With this particular platform, we have begun testing the role of other genes in uveal melanoma disease progression and metastasis and have found an important role for the endothelin G protein coupled receptor (Ednrb).
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3. Metalloproteases in melanocytes
In addition to the uniformly dark mouse mutants, my lab has also studied mutant mice with other varieties of skin pigmentation abnormalities, such as freckling and hypo-pigmentation. While some melanocytic nevi are precursor lesions for cutaneous melanoma, freckles remain benign and arise through an as yet undetermined mechanism. Using forward genetics in a spontaneous freckled mouse mutant named Pied, we identified the metalloprotease, Adam10. Adam10 is the main protease that cleaves the Notch receptor. ADAM10 mutations in humans are now known to underlie Reticulate Acropigmentation of Kitamura. This illustrates the powerful synergism of high throughput human sequencing combined with classical mouse mutagenesis to identify disease causing mutations in rare disorders. In addition, we discovered that another family member, Adamts9, is mutant in mice with patches of congenital skin hypo-pigmentation (Und3 and Und4). In collaboration with Dr. Christopher Overall at UBC, we mapped the proteome in the skin of Adamts9 mutant mice and found changes in the extracellular matrix that appear to impair melanocyte survival.
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Tharmarajah, G., Faas, L., Reiss, K., Saftig, P., Young, A., and Van Raamsdonk, C. D. (2012). Adam10 haploinsufficiency causes freckle-like macules in
Hairless mice. Pigment Cell and Melanoma Research 25, 555-65.
Tharmarajah, G., Eckhard, U., Jain, F., Marino, G., Prudova, A., Urtatiz, O., Fuchs, H., de Angelis, M.H., Overall, C.M., Van Raamsdonk, C.D. (2018). Melanocyte
development in the mouse tail epidermis requires the Adamts9 metalloproteinase. Pigment Cell and Melanoma Research 31, 693-707.
4. Connections between melanocyte development and melanoma
Melanocytes arise in at least two waves in the trunk during development. The first wave derives directly from the neural crest and migrates along the dorsal-lateral pathway. The second wave arises from multipotent neural crest cells lining developing peripheral nerves. Both lineages must migrate through the dermis to reach their final destination in the skin, eyes or central nervous system. We are interested in how these developmental pathways might be related to oncogene specificity in different melanoma subtypes. A clearer understanding of the developmental origins of cells producing each melanoma subytpe might help inform diagnosis and prognosis in melanoma patients. We have studied the effects of conditional expression of oncogenes in specific melanocytic lineages in mice and found that there are indeed differences in the frequency and types of melanocytic lesions that are produced.
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Deo, M., Huang, J. L., Fuchs, H., De Angelis, M. H., and Van Raamsdonk, C. D. (2013). Differential effects of neurofibromin gene dosage on melanocyte
development. Journal of Investigative Dermatology 133, 49-58.
Urtatiz, O., Samani, A.M.V., Kopp, J.L., and Van Raamsdonk, C.D. (2018). Rapid melanoma induction in mice expressing oncogenic Braf V600E using Mitf-
cre. Pigment Cell and Melanoma Research. 31, 541-544.
Urtatiz, O., Cook, C., Huang, J.L.Y., Yeh, I., and Van Raamsdonk, C.D. (2020) GNAQ Q209L expression initiated in multipotent neural crest cells drives
aggressive melanoma of the central nervous system. Pigment Cell and Melanoma Research 33 (1), 96-111.