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Cancer Cell. 2013 Oct 14;24(4):466-80. doi: 10.1016/j.ccr.2013.08.018. Epub 2013 Sep 26.

A switch in the expression of embryonic EMT-inducers drives the development of malignant melanoma.

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Inserm UMR-S1052, Centre de Recherche en Cancérologie de Lyon, 69008 Lyon, France; CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, 69008 Lyon, France; LabEX DEVweCAN, 69008 Lyon, France; University Lyon I, 69008 Lyon, France; Université de Lyon, 69000 Lyon, France; Centre Léon Bérard, 69008 Lyon, France.


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.

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