Phenotype plasticity mediated by EMT-inducing transcription factors contributes to melanoma development and resistance to treatments

Orateur : Julie CARAMEL (CRCL, Lyon)

Metastatic melanoma is an aggressive neural-crest derived skin tumor that displays a high degree of inter and intratumoral heterogeneity. Melanoma cells reversibly shift between a proliferative and an invasive state according to a “phenotype-switching” model controlled by the MIcrophthalmia-associated Transcription Factor (MITF). Despite recent progress provided by BRAF/MEK targeted therapy and immunotherapies (anti-PD1) for the treatment of metastatic melanoma, primary and acquired resistances still occur. While resistance may be driven by genetic alterations, recent evidence suggests the major contribution of phenotypic adaptations, mediated by transcriptional and epigenetic processes that remain poorly characterized. New predictive biomarkers of response to treatments and new combination therapies for the treatment of metastatic melanoma are thus urgently needed. Our results show that epithelialmesenchymal- transition inducing transcription factors (EMT-TF) play a major oncogenic role in melanoma by regulating cancer cell plasticity (Caramel et al., Cancer Cell, 2013). In particular, ZEB1 regulates phenotype switching of melanoma cells towards a MITFlow invasive and stemness state associated with resistance to MAPK targeted therapy (Richard et al., EMBO Mol Med, 2016).

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