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Oncogenic GNAQ and BRAF in epidermal versus non-epidermal melanocytes

University of British Columbia

Melanocytic neoplasms represents a group of biologically distinct subtypes that display a wide phenotypic variation. An integrative taxonomy of melanocytic neoplasms have grouped them into two major clades: those that arise from epithelium-associated melanocytes and those that arise from non-epithelium-associated melanocytes. In sites with an epithelial component, e.g. the skin epidermis or conjunctiva of the eye, activating BRAF mutations are frequently found. In contrast, activating GNAQ/11 mutations are virtually absent in those lesions, and instead are frequently found in lesions located in non-epithelial sites, such as the skin dermis, uveal tract of the eye, or meninges, where melanocytes interact with mesenchymal cells instead of epithelial cells. Why does this pattern occur? This question has been the overarching focus of this thesis, with experiments addressing how melanocytes respond to BRAF^V600E and GNAQ^Q209L oncogenes in epithelial and non-epithelial associated melanocytes. It has been suggested that the melanocytic lineage might comprise different subtypes of melanocytes that respond to activation of distinct pathways. Whether this differential response is due to unappreciated differences in the developmental migration of epithelial versus non-epithelial melanocytes, or to different microenvironmental cues sent to mature melanocytes located in different sites has been undetermined. In this dissertation, we found evidence that both developmental processes and microenvironmental cues influence the ability of oncogenes to drive melanocyte transformation. In chapter 2, we characterized a new mouse model for BRAF^V600E driven melanoma targeting melanocytes residing in both epithelial and non-epithelial tissues. Interestingly, non-epithelial melanocytes in the eye or leptomeninges did not respond to oncogenic Braf^V600E signaling. In chapter 3, we found that the timing of GNAQ^Q209L mutation during development influences the subtype of melanoma produced. In chapter 4, we found that the response of mature melanocytes to different oncogenic stimuli is flexible and depends upon environmental signals. Epidermal melanocytes survive poorly in the face of GNAQ^Q209L signaling because paracrine signals from keratinocytes coupled with GNAQ^Q209L signaling make melanocytes more sensitive to cellular stress. They are then lost through apoptosis. However, interactions with fibroblasts have the opposite effect, increasing the ability of GNAQ^Q209L to promote melanocyte transformation.

Text

2021-09-30

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/71766

Medical Genetics

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/