Abstract 1144: Cell plasticity mediated by EMT-inducing transcription factors contributes to melanoma development

Abstract

Background: Embryonic transcription factors inducers of Epithelial to Mesenchymal Transition (EMT-TFs) are frequently reactivated during tumorigenesis. In addition to promoting metastasis in carcinoma, they favor neoplastic transformation of epithelial cells by enabling escape from oncogene-induced senescence and apoptosis and providing cells with stem-like properties. We recently unveiled different regulation and function of EMT-TFs in melanoma, a highly metastatic neural crest-derived cancer. We observed a switch in expression 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 cooperate with BRAFV600E oncogene to induce neoplastic transformation of melanocytes. This switch in EMT-TF expression represents a novel independent factor of poor prognosis in patients with malignant melanoma (Caramel et al, Cancer Cell, 2013). We further investigated the oncogenic properties of TWIST1 and ZEB1 in melanoma development and analyzed the crosstalk with the master regulator of melanoma phenotypic plasticity, the microphthalmia-associated transcription factor MITF. Methods: We first analysed the expression of MITF and TWIST1/ZEB1 in melanoma cell lines and human melanoma specimens by immunohistochemistry. We then studied the role of TWIST1 in melanoma progression in vivo by crossing conditional Twist1 transgenic mice with BRAFV600E/TyrCreERT2 mice. Results: Our data suggest that EMT-TFs control melanoma cell plasticity by modulating MITF level and the associated pathways. High MITF levels maintain the differentiated status of melanocytes, while reduction of MITF expression results in the transition to proliferative and invasive/stem states. TWIST1 and ZEB1 cooperate with BRAF in downregulating MITF concomitantly with the induction of invasion-associated gene signatures. A correlation of MITF expression with TWIST1 and ZEB1 is observed in human melanoma specimens at the intratumoral level. Moreover, while Twist1 enables BRAFV600E-induced senescence escape in primary mouse melanocytes, monitoring of the development of nevi and melanomas in the BRAFV600E mouse model showed more aggressive features in BRAFV600E/Twist1 mice compared to BRAFV600E control mice. Conclusion: Collectively, these data highlight crucial roles for TWIST1 and ZEB1 in promoting cell dedifferentiation and plasticity of non-epithelial cells. By regulating MITF-dependent phenotype switching they contribute to malignant progression of melanoma. Therefore, targeting the EMT-TF network represents an attractive strategy for metastatic melanomas that invariably develop resistance to BRAFV600 targeted therapy. Citation Format: Julie Caramel, Geoffrey Richard, Michelle Houang, Arnaud de la Fouchardiere, Lionel Larue, Richard Marais, Stephane Dalle, Eugene Tulchinsky, Stephane Ansieau, Alain Puisieux. Cell plasticity mediated by EMT-inducing transcription factors contributes to melanoma development. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1144. doi:10.1158/1538-7445.AM2014-1144