Mechanisms of UV-Mediated Melanoma Development

摘要 预防黑色素瘤的生物过程通常是成功的。因此，要了解黑色素瘤 病因学：我们必须找出导致肿瘤发生的这些机制中的缺陷。这项提议将澄清 对抗紫外线损伤和确定肿瘤发生后果的细胞机制的缺陷 黑素细胞色素的产生。我们的研究将通过以下方式提高对黑色素瘤病因的机制理解 揭示了阻止紫外线致癌的生理过程中的差距。 我们假设黑色素瘤的进展受黑色素产生的影响，并受 特定于启动紫外线波长的未解决的DNA损伤的持久性。为了检验这一假设，我们 将定义全光谱(UVA/B)和分区太阳辐射(UVA或UVB)如何影响 在基因相关的BRAF和NRAS突变小鼠模型中黑色素瘤的进展。我们会澄清 由每个紫外线光谱和癌基因驱动的肿瘤中丰富的转录和突变模式，并使用 这些信息定义紫外线损伤如何逃脱修复(目标1)。接下来，我们将把我们的模型交叉到Eumelanic (黑色)、无色素性(白化)或黑色素性(红色/黄色)等位基因，以确定黑色素如何影响 促BRAF和NRAS突变型黑色素瘤的形成、发展及免疫治疗反应 不同的紫外线光谱(目标2)。从这些实验中获得的知识将有助于黑色素瘤的发展 超越防晒霜的预防措施，包括减少紫外线致癌的干预措施 暴露或降低具有更多光敏皮肤类型的人患黑色素瘤的风险。

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.