Initiation and progression of UV-induced melanocytic lesions in a mouse model of melanoma

Authors

• HT Michael
• CP Day
• A Michalowski
• MR Zaidi
• PS Meltzer
• G Merlino

Abstract

Melanoma is the deadliest form of skin cancer. UV-exposure is believed to be important in the development of melanocytic nevi (moles) and melanoma, but the mechanism is poorly-understood. Nevi are typically benign lesions which develop in the first few decades of life. Progression of nevi is rare, but up to half of melanomas arise from nevi. Most nevi have activation of the MAP kinase pathway through activating mutations in BRAF or NRAS, but nearly 1/3 of melanomas lack a known dominant driver mutation. There are no biomarkers or histologic features predict which nevi might progress. Without genetic engineering, mice have follicle-restricted melanocytes and are resistant to formation of melanoma. Our HGF mouse model has a “humanized” junctional distribution of melanocytes and the iDCT-GFP background allows us to monitor lesions in vivo with fluorescent imaging of melanocyte-specific GFP. Following a single, relevant neonatal UV-exposure, HGFtg/-; INK4A+/- iDCT-GFP mice develop small, discrete nevi. Some nevi resume growth within 6-12 months and eventually progress to melanoma with a radial growth phase followed by a vertical growth phase. The melanocytic lesions are histologically similar to human melanocytic lesions, and are transplantable into syngeneic mice. Exome sequencing of stable nevi, growing atypical nevi and melanomas show a predominance of mutations consistent with UV exposure with 2-3x more nonsynonymous coding mutations in melanomas than nevi. Recurrent mutations present in both nevi and melanomas provide information about the role of UV in the initiation of melanocytic lesions and into mechanisms of progression of non-BRAF, non-NRAS melanoma.

Scientific Focus Area: Cancer Biology

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