Catherine van Raamsdonk

My lab studies cancer and development, with a focus on the pigment producing cells, called melanocytes. We have worked on many different projects over the years, however, a major theme has been the tumour promoting effects of unregulated G-protein signaling.

1. Identification of GNAQ/GNA11 as human oncogenes

When I began working in this field, the somatic mutations that drive melanoma in the eyes, dermis and central nervous system were unknown. To address this, we mapped and cloned ENU-generated mutations that cause hyper-pigmentation of the dermis in mice. This identified the Gnaq and Gna11 genes as important regulators of melanocyte growth in fibroblast rich environments. Gnaq and Gna11 encode members of the q class of G-protein alpha subunits involved in mediating signals between G-protein coupled receptors (GPCRs) and downstream effectors. The mouse dark dermis mutations that we identified caused mild Gq/11 protein hyper-activity. This work showed that genes that regulate skin versus hair pigmentation are distinct and was exciting because G proteins are important signaling components for many cell types.

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, 961-8.

At UBC as a PI, my first project was to determine whether the GNAQ or GNA11 homologs were mutant in human melanomas. We sequenced the genes in many samples. As suspected, GNAQ and GNA11 were mutant in ocular melanomas (called uveal melanoma) and blue nevi (intra-dermal pigmented lesions). The mutations occurred specifically at one of two codons and resulted in constitutive activation of Gq/11 signaling. Almost all ocular melanomas and blue nevi had one or the other gene mutant. This indicated that therapies that target the Gq/11 pathway could be broadly suitable for people with ocular melanoma and pigmented dermal lesions.

Van Raamsdonk, C. D., Bezrookove, V., Green, G., Bauer, J., Gaugler, L., O'brien, J. M., Simpson, E. M., Barsh, G. S., and Bastian, B. C. (2009). Frequent somatic mutations of GNAQ in uveal melanoma and blue naevi. Nature 457, 599-602.

Van Raamsdonk, C. D.*, Griewank, K. G., Crosby, M. B., Garrido, M. C., Vemula, S., Wiesner, T., Obenauf,   A. C., Wackernagel, W., Green, G., Bouvier, N., Sozen, M.M., Baimukanova, G., Roy, R., Heguy, A., Dolgalev, I., Khanin, R., Busam, K., Speicher, M.R., O'Brien, J., Bastian, B.C.*Co-corresponding authors (2010). Mutations in GNA11 in uveal melanoma. New England Journal of Medicine 363, 2191-9.

2. Engineering mice to express oncogenic GNAQ

To build on these discoveries and provide a pre-clinical platform, my lab genetically engineered a mouse line that can express a  constitutive active version of human GNAQ in any cell type of interest using Cre-loxP technology. We crossed in a Cre line expressed in melanocytes and this generated ocular melanoma within 12 weeks. This result emphasized the strength of the GNAQ oncogene in transforming melanocytes located in the eye.

Huang, J.L., Urtatiz, O., Van Raamsdonk, C.D. (2015). Oncogenic G protein GNAQ induces uveal melanoma and intravasation in mice. Cancer Research. Aug 15; 75(16):3384-97.

We have used the mouse strain to investigate why GNAQ and GNA11 mutations are almost never found in melanomas arising in the epidermis in the skin. We found that paracrine signals from keratinocytes block the oncogenic effects of GNAQ, and actually lead to reduced survival of GNAQ-expressing melanocytes. This work suggests that there are signaling molecule(s) that can shut off the oncogenic effects of GNAQ in melanocytes, which could be a less toxic therapeutic strategy for ocular and intra-dermal melanoma.

Urtatiz O, Haage A, Tanentzapf G, and Van Raamsdonk CD. (2021). Crosstalk with keratinocytes causes GNAQ oncogene specificity in melanoma. Elife. doi: 10.7554/eLife.71825.

3. Oncogenic GNAQ transforms Schwann cells

Melanocytes arise in at least two waves during development. The first wave derives directly from the neural crest cell population and migrates just under the epidermis. The second wave arises from Schwann cell precursors lining developing peripheral nerves. Thus, Schwann cells and melanocytes share a developmental origin. A number of human disorders have both Schwann cell and pigmentary abnormalities, such as the Cafe au lait macules in Neurofibromatosis type 1. We are interested in this relationship between Schwann cells and melanocytes in development and disease. Recently, we discovered that the GNAQ oncogene also transforms Schwann cells, producing a tumour that is very similar to neurofibroma in Neurofibromatosis type 1.

Longakit, A.N., Urtatiz, O., Luty, A., Zhang, C., Hess, C., Yoo, A., Bourget, H. and Van Raamsdonk, C.D. (2025). Loss of NF1 accelerates uveal and intra-dermal melanoma tumorigenesis and oncogenic GNAQ transforms Schwann cells. Cancer Research Communications. doi: 10.1158/2767-9764.CRC-24-0386.

Pigment Cells: A Window Into Genetics, Evolution, and Human Health

Studying pigment cells is a lot of fun, because the field bridges developmental biology, human and animal genetics, human diversity and evolution. With the knowledge we gain, we can better understand human health, diseases such as melanoma, and adaptations to diverse environments.

• We study normal mammalian pigment cells, called melanocytes, as they grow and migrate in mouse embryos.
• Using mice with mutations in key genes, we investigate how melanocytes contribute to the pigmentation of the skin and eyes, and do interesting things like make freckles. We model melanoma in genetically engineered mice, where all stages of tumor development can be studied and potential therapeutics can be tested.
• We identify the molecular steps that transform normal human melanocytes into melanoma in the eye, using 'omics approaches from the genome to the proteome.