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.
Significance: Development of drug resistance is a major cause of melanoma therapy failure. The role of MITF in melanoma response to therapy has been discussed controversially, which can be explained, at least in part, through the rheostat model linking MITF activity to cell proliferation. Heterogeneity is widely associated with therapy resistance, however, whether cell phenotype switching, mediated by MITF, is responsible for treatment resistance is not known. Our findings provide an in-depth mechanistic understanding of the MITF-mediated regulation of cell cycle behavior and physical regulation of the tumor architecture. As MITF is not amenable to direct drug targeting, the identification of mediators of MITF-triggered functional heterogeneity reveals novel targets that can be deployed to control this phenomenon.