Abstract A19: Expression of BRAFV600E in melanocytes induces Schwannian differentiation in vivo

Abstract

Abstract Transgenic mice expressing BRAFV600E targeted to melanocytes via the tyrosinase promoter display hyperpigmentation of the skin, ears, tail, and paws, as well as profound graying of the hair, benign melanocytic hyperplasias and a low frequency of spontaneous melanomas on a mixed genetic background. In order to investigate the underlying mechanism of BRAFV600E-induced alterations in skin and hair, mice were backcrossed extensively onto a C57BL/6 background. Backcrossed BRAFV600E mice retained the phenotype of mixed background transgenic animals with respect to skin hyperpigmentation as well as premature hair graying. Analysis of skin samples from mice of different ages revealed an accumulation and mislocalization of hyperproliferative melanocytes, suggesting a developmental defect in melanocyte homing to hair follicles in response to activated BRAF. Moreover, melanocytic lesions in the skin developed into benign tumors resembling nerve sheath tumors of Schwannian origin, presumably due to the phenotypic switching of melanocytes into Schwann cells in response to chronic BRAFV600E stimulation. These benign tumors seldom progressed to melanoma in the absence of Akt pathway activation. A role for Akt activation in repressing the Schwannian differentiation program is suggested, as treatment of melanoma-derived cell lines with the Akt inhibitor MK-2206 results in elevated expression of Schwannian lineage markers at the transcript level. Therefore, in addition to induction of oncogene-induced senescence, eliciting lineage-switching from melanocytes into Schwann cells in response to oncogenic BRAF represents a potential tumor suppression mechanism to protect melanocytes from transformation, and repression of this phenotypic switch via activation of the Akt pathway may facilitate the ability of BRAFV600E to drive melanomagenesis. Citation Format: Jodie R. Pietruska, Chi Luo, Philip W. Hinds. Expression of BRAFV600E in melanocytes induces Schwannian differentiation in vivo. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Melanoma: From Biology to Therapy; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(14 Suppl):Abstract nr A19.