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

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• 作者：Julie Caramel ; Eftychios Papadogeorgakis ; Louise Hill ; Gareth?J. Browne ; Geoffrey Richard ; Anne Wierinckx ; Gerald Saldanha ; Joy Osborne ; Peter Hutchinson ; Gina Tse ; Jo?l Lachuer ; Alain Puisieux ; J.?Howard Pringle ; St¨¦phane Ansieau ; Eugene Tulchinsky
• 刊名：Cancer Cell
• 出版年：2013
• 出版时间：14 October, 2013
• 年：2013
• 卷：24
• 期：4
• 页码：466-480
• 全文大小：5752 K

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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.