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

Julie Caramel, Eftychios Papadogeorgakis, Louise Hill, Gareth J. Browne, Geoffrey Richard, Anne Wierinckx, Gerald Saldanha, Joy Osborne, Peter Hutchinson, Gina Tse, Joël Lachuer, Alain Puisieux, J. Howard Pringle, Stéphane Ansieau, Eugene Tulchinsky

Cancer Cell, Volume 24, Issue 4, 14 October 2013, Pages 466–480

Summary

Aberrant 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.