Abstract B11: Mouse models of melanoma driven by oncogenic NRAS
Authors: Pedersen Malin , Viros Amaya , Marais Richard 
Published: May 2015

Abstract
Melanoma is the most deadly form of skin cancer and is a disease that is rising in incidence. Approximately 20% of all melanomas harbor activating mutations in NRAS. We previous used inducible-conditional approaches to express oncogenic NRAS (NRASG12D) at physiological levels in mouse melanocytes. When expressed in adult mouse melanocytes, NRASG12D induced skin darkening and blue nevus-like lesions but did not induce cutaneous melanoma. When expressed during embryogenesis, NRASG12D induced congenital nevi and leptomeningeal melanocytosis that replicated the cardinal features of human neurocutaneous melanosis. To extend these studies, we have examined how ERK signal strength affects NRASG12D-driven melanomagenesis. We previously demonstrated that kinase-dead BRAF drives paradoxical hyper-activation of ERK downstream of oncogenic RAS, so to investigate how ERK signal strength affects RAS-driven melanomagenesis, we expressed NRASG12D and kinase-dead BRAF (BRAFD594A) in adult mouse melanocytes. BRAFD594A did not induce any skin lesions. In accordance with our previous study, NRASG12D induced paucicellular nevi composed of pigmented dendritic melanocytes in the papillary and superficial reticular dermis. These lesions resembled nevus of Ota, but none of the mice developed melanoma. When BRAFD594A and NRASG12D were co-expressed, we observed the paucicellular nevi seen in NRASG12D mice, but additionally, we observed a proliferation of nevi in the deep reticular dermis, the hypodermis and enveloping the cutaneous adnexae. The cells in these lesions were heavily pigmented epitheliod or ovoid melanocytes and the lesions were reminiscent of dermal melanocytosis with scattered foci of blue nevi. More importantly, these mice developed melanoma that presented with two distinct histological types. The majority of the tumours presented as hypo-pigmented lesions that extended from the upper dermis into the subcutaneous layers, leaving a narrow or absent grenz zone and frequent focal ulceration. They were amelanotic and the predominant cells were undifferentiated atypical spindle melanocytes. The tumours replaced the normal architecture of the upper dermis, invading the adjacent and subcutaneous structures, and occasionally presented nevi remnants at their poorly defined borders. Less common, the tumours were hyper-pigmented lesions that arose in the deep reticular dermis, leaving a wide grenz zone and only occasionally ulcerating the epidermis. The tumour cells were predominantly heavily pigmented, pleomorphic epithelioid melanocytes, abutting into the deeper layers of the subcutis and the lesions resembled animal-type melanoma in humans. Thus, we show that ERK signal strength is critical for NRAS-driven melanomagenesis and this pathway drives different types of lesion that resemble human nevi and melanoma.
Citation Format: Malin Pedersen, Amaya Viros, Richard Marais. Mouse models of melanoma driven by oncogenic NRAS. [abstract]. In: Proceedings of the AACR Special Conference on RAS Oncogenes: From Biology to Therapy; Feb 24-27, 2014; Lake Buena Vista, FL. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(12 Suppl):Abstract nr B11. doi: 10.1158/1557-3125.RASONC14-B11