Abstract Of the four molecular subtypes of melanoma (BRAF, NRAS, NF1, and triple WT), NRAS mutant tumors are notoriously more aggressive and challenging to treat. The frequent occurrence of NRAS mutations in benign, congenital nevi suggests that these genetic alterations are early events in melanoma genesis. Since NRAS mutant nevi can remain indolent for years, or even a lifetime, secondary genetic events must be required to drive melanoma initiation. Ultraviolet (UV) light, a major risk factor for melanoma, is known to directly damage DNA and alter the skin microenvironment. Therefore, we hypothesized that the cell-extrinsic and intrinsic events triggered by UV exposure would cooperate with NrasQ61R mutations to drive melanoma formation in vivo. To test this hypothesis we employed a genetically engineered mouse model (i.e. TpN61R) that combines CRE-inducible expression of NrasQ61R with the loss of p16INK4a in melanocytes. Following neonatal CRE induction, we exposed TpN61R mice to a single, nonerythemic dose of UVB radiation and monitored them for the development of melanoma. Exposure to UVB radiation dramatically reduced the melanoma-free survival of TpN61R mice by 80% and increased tumor multiplicity (average 1.2 to 3.4 tumors/mouse); however, it had no impact on tumor growth rates, overall skin proliferation, immune infiltration, or vascularity. To test the respective roles of NrasQ61R and p16INK4a loss in UV-induced melanoma genesis, we generated mice with either melanocytic NrasQ61R expression or p16INK4a loss. Mice with p16INK4a loss alone did not develop tumors in the presence or absence of UV. By contrast, in UV treated TN61R mice, NrasQ61R was sufficient to initiate melanoma formation, albeit with a 66% longer latency than UV exposed TpN61R animals (9.14wks vs. 5.5wks). To determine if NrasQ61R mutations had to be present at the time of UV exposure to drive early melanoma formation, TpN61R mice were exposed to UV prior to CRE activation. Even when NrasQ61R expression was induced three days after UV exposure, melanoma formation was rapidly accelerated. Therefore, NRAS mutations do not need to be present at time of UV exposure to promote early melanoma formation. Genomic analyses comparing spontaneous and UV-induced TpN61R melanomas failed to uncover common secondary mutations that explain the exquisite cooperativity between NrasQ61R and UV light in driving melanoma formation. For this reason, we sought to identify UV-induced, cell-extrinsic factors that might facilitate the initiation of NrasQ61R mutant melanomas via cytokine profiling. Through these analyses we identified UV-induced pro-inflammatory cytokines that could be therapeutically targeted to limit the initiation of NRAS-mutant melanomas. Together, this work explains why UV exposure is such a significant risk factor for melanoma and provides original mechanistic insight into how this deadly disease might be prevented. Citation Format: Rebecca C. Hennessey, Andrea M. Holderbaum, James E. Gillahan, Conor Delaney, Xing Tang, Raleigh Kladney, Christin E. Burd. Ultraviolet light cooperates with NrasQ61R mutations to drive malignant melanoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2685.
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Dec 29, 2016
Anika Zafiah M Rus + 2
Open Access
