Despite the success of targeted and immune therapies, many patients with advanced melanoma still die due to therapy resistance. Drug resistance is a major challenge for effective melanoma therapy. Plasticity of solid cancer plays a critical role in shaping treatment response. What determines the occurrence of phenotypically distinct tumour cell domains in solid cancers is poorly understood. Utilizing in vitro and in vivo three-dimensional models, we show that in melanoma spatial organization of plasticity is dictated by the expression and activity of the lineage-survival oncogene microphthalmia-associated transcription factor (MITF). Mechanistically, we reveal that MITF controls extracellular matrix (ECM) composition and decreases ECM organization. This leads to reduction of Rho-ROCK-myosin signalling-driven mechanotransduction through poor focal adhesion maturation and reduced contractility of the actin cytoskeleton. The resulting altered tumour microarchitecture and structural relaxation decrease tumour solid stress and subsequently p27Kip1 expression, ultimately reducing plasticity. Consequently, selective inhibition of ROCK phenocopies the effect of MITF over-expression, demonstrating the importance of cell-ECM crosstalk in this process.
In summary, our findings place tumour cell-ECM crosstalk resulting in altered tumour microarchitecture and ROCK-driven mechanotransduction as a central driver of melanoma cell plasticity. Indeed, we show that resistance to targeted therapies is often cell cycle dependent, underlining the importance of tumour cell plasticity for successful targeted therapy. Moreover, we show that structural relaxation and decreased tumour solid stress allow deeper immune cell penetration, and thus provide potential for therapeutically targeting this phenomenon for improved immune checkpoint therapy.