Oral communication, PS5 / C71

Official XXIst International Pigment Cell Conference website - 21-24 Sept 2011, Bordeaux - France | updated: September 04 2011

Hypoxia and MITF control metastatic behaviour in mouse and human melanoma cells

Melanomas are very aggressive neoplasms with notorious resistance to therapeutics. It was recently proposed that the remarkable phenotypic plasticity of melanoma cells allows for the rapid development of both resistance to chemotherapeutic drugs and invasive properties. Indeed, the capacity of melanoma cells to form distant metastases is the main cause of mortality in melanoma patients. Therefore, the identification of the mechanism controlling melanoma phenotype is of paramount importance. We previously identified MITF, the master regulator of melanocyte differentiation, and p27, a CDK inhibitor, as the key molecular switches that control the transition between melanoma-initiating cells and their differentiated progeny. In the present report, we show that deletion of MITF, the master gene in melanocyte differentiation, is sufficient to increase the metastatic potential of mouse and human melanoma cells. MITF silencing also increases fibronectin and Snail, two mesenchymal markers that might explain the increased invasiveness in vitro and in vivo. Furthermore, ablation of this population by forskolin-induced differentiation or MITF forced expression dramatically decreases tumour formation, indicating that eradication of low-MITF cells is an appealing strategy to cure melanoma. Moreover, we demonstrate that a hypoxic micro-environment decreases MITF expression through an indirect, HIF1α dependent transcriptional mechanism and increases the tumorigenic and metastatic properties of melanoma cells. Our results reveal a hypoxia-HIF1alpha-MITF cascade controlling the phenotypic plasticity in melanoma cells and favouring metastasis development. Targeting this pathway might be helpful in the design of new anti-melanoma therapies.

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