A Switch in the Expression of Embryonic EMT-Inducers Drives the Development of Malignant Melanoma

• The EMT-TF reprogramming predicts poor outcome in melanoma patients
• The EMT-TF reprogramming is dependent on ERK activity and involves FRA1
• ZEB1 and TWIST1 are oncogenic; ZEB2 and SNAIL2 are oncosuppressive in melanoma
• The antagonistic properties of EMT-TFs mirror their opposing effects on MITF

SummaryAberrant expression of embryonic epithelial-mesenchymal transition-inducing transcription factors (EMT-TFs) in epithelial cells triggers EMT, neoplastic transformation, stemness, and metastatic dissemination. We found that regulation and functions of EMT-TFs are different in malignant melanoma. SNAIL2 and ZEB2 transcription factors are expressed in normal melanocytes and behave as tumor-suppressor proteins by activating an MITF-dependent melanocyte differentiation program. In response to NRAS/BRAF activation, EMT-TF network undergoes a profound reorganization in favor of TWIST1 and ZEB1. This reversible switch cooperates with BRAF in promoting dedifferentiation and neoplastic transformation of melanocytes. We detected EMT-TF reprogramming in late-stage melanoma in association with enhanced phospho-ERK levels. This switch results in E-cadherin loss, enhanced invasion, and constitutes an independent factor of poor prognosis in melanoma patients.