Abstract 1049A: Deregulation of MITF in the context of inactive MC1R leads to melanocyte transformation

Abstract

MC1R, the cAMP pathway and the response to solar UV are all elements involved in the growth, differentiation and survival of melanocytes and in malignant melanoma. Here we present a model of melanomagenesis based on the forced expression of MITF-M in the context of MC1R-inactivating variants in a way not dependent on sun exposure. We demonstrate that lentiviral transduction of MITF-M alone leads to consistent transformation of the Hermes4C cell line with inactive MC1R, but not the Hermes3C cell line having a wild type background. Hermes 4c cells transduced with MITF-M are able to form tumors in mice. We mapped MITF binding to chromatin and found that 4C cells displayed enhanced MITF chromatin binding compared to 3C. Expression analysis revealed that the altered binding pattern leads to enhanced transcription of epithelial to mesenchymal transition genes and consequent repression of key melanocyte-specific genes e.g. involved in pigmentation in the background of inactive MC1R. We observed a marked deregulation of AXL and EGFR, which is accompanied by downregulation of PTEN and increased phosphorylation of ERK and PI3K-AKT pathway. In conclusion, we show that MITF-M is a molecular switch in the context of MC1R-inactivating variant which leads to cell reprogramming and melanomagenesis. Citation Format: Tine Norman Alver, Timothy J. Lavelle, Karen-Marie Heintz, Patrik Wernhoff, Vegard Nygaard, Geir F. Øy, Sigurd L. Bøe, Alfonso Urbanucci, Eivind J. Hovig. Deregulation of MITF in the context of inactive MC1R leads to melanocyte transformation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1049A.