Antagonistic functions of EMT-inducers in melanoma development: implications for cancer cell plasticity

Abstract

EMT-inducing transcription factors (EMT-TFs) of the SNAIL, TWIST and ZEB families are frequently reactivated during tumorigenesis. In carcinoma, in addition to promoting metastasis, they favor neoplastic transformation of epithelial cells by enabling escape from failsafe programs and providing cells with stem-like properties. We recently unveiled different functions and regulatory mechanisms of EMT-TFs in melanoma, a highly metastatic neural crest-derived cancer. A switch in expression is observed from SNAIL2 and ZEB2, which are expressed in melanocytes and behave as oncosuppressive proteins to TWIST1 and ZEB1, which are aberrantly reactivated in melanoma and foster neoplastic transformation of melanocytes. This reversible switch in EMT-TF expression driven by a MEK-ERK-FRA1 pathway represents a novel independent factor of poor prognosis in patients with malignant melanoma. We herein discuss cell type specific biological functions of EMT-TFs in terms of cancer cell plasticity.