Biological processes that guard against melanoma are generally successful. Thus, to understand melanoma etiology we must identify the flaws in these mechanisms that lead to tumorigenesis. This proposal will elucidate deficiencies in the cellular mechanisms that combat UV damage and define the tumorigenic consequences of melanocyte pigment production. Our studies will improve mechanistic understanding of melanoma etiology by revealing gaps in the physiological processes that block UV carcinogenesis. We hypothesize that melanoma progression is influenced by melanin production and accelerated by the persistence of unresolved DNA lesions specific to the initiating UV wavelength. To test this hypothesis we will define how full-spectrum (UVA/B) and partitioned solar irradiation (UVA or UVB) influence the onset and progression of melanoma in genetically relevant, Braf- and Nras-mutant mouse models. We will elucidate transcriptional and mutational patterns enriched in tumors driven by each UV spectrum and oncogene, and use this information to define how UV lesions escape repair (Aim 1). Next, we will cross our models to eumelanotic (black), amelanotic (albino) or pheomelanotic (red/yellow) alleles to determine how melanin impacts the formation, progression and immunotherapeutic response of Braf- and Nras-mutant melanomas accelerated by different UV spectra (Aim 2). Knowledge gained from these experiments will aid in the development of melanoma preventatives that progress beyond sunscreens, including interventions that mitigate UV carcinogenesis after an exposure or reduce melanoma risk in individuals with more photosensitive skin types.
Major risk factors for melanoma include fair skin and a history of sunburns, yet incomplete understanding of how different skin pigments and types of ultraviolet sunlight (UVA, UVB) contribute to melanoma progression has hindered efforts to curb disease incidence. In this application, we will use models genetically representative of human melanoma to determine how different skin pigments and forms of UV light contribute to melanoma progression. This work will identify deficiencies in the biological mechanisms that protect us from the sun, which could be mitigated to improve melanoma prevention strategies and patient outcomes.
