537 Functional melanoma cell heterogeneity is regulated by MITF-dependent cell-matrix interactions

Phenotypic and functional cancer cell heterogeneity limits the efficacy of targeted and immuno-therapies. The transcription factor MITF is known to regulate melanoma cell plasticity and, consequently, response to drugs. However, the underlying mechanisms of this phenomenon remain incompletely understood. Here, we show that MITF levels control functional melanoma cell heterogeneity by fine-tuning the ability to contract the extracellular matrix, the maturation of focal adhesions and ROCK-mediated melanoma cell contractility. Modulation of MITF expression alters extracellular matrix organization, melanoma cell morphology and solid stress in three-dimensional melanoma spheroids, thereby accounting for spatial differences in cell cycle dynamics. Together, our data identify MITF as a master regulator of the melanoma micro-architecture and point towards novel targeting strategies for cancer cell heterogeneity.