Mechanisms of UV-Mediated Melanoma Development

ABSTRACT
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.

Grant Number: 5R01CA237213-05
NIH Institute/Center: NIH
Principal Investigator: Christin Burd