Extracellular matrix stiffness determines the phenotypic behavior of dedifferentiated melanoma cells through a DDR1/2-dependent YAP mechanotransduction pathway

Extracellular matrix (ECM) stiffening is a biophysical hallmark of solid tumors. Cutaneous melanoma is an aggressive malignancy characterized by high heterogeneity and phenotypic plasticity in which melanoma cells switch from a proliferative and differentiated phenotype to an invasive, dedifferentiated and therapy-resistant state. The impact of ECM stiffness on the diverse cellular phenotypes of melanoma remains poorly defined. Here, we show that melanoma cell subpopulations differ in their responses to mechanical signals. Compared to melanocytic cells, dedifferentiated cells exhibited increased proliferation, migration, and resistance to MAP kinase-targeted therapy when seeded on stiff collagen. In contrast, a soft ECM impaired their proliferation and migration, and sensitized them to targeted therapy. The mechanosensitivity of dedifferentiated cells relies on collagen receptors DDR1 and DDR2, which control cytoskeleton reorganization and YAP mechanosignaling. Our results thus reveal that phenotypic plasticity endows dedifferentiated melanoma cells with increased addiction to ECM stiffness and implicate DDR1/2-YAP-dependent signaling in this aggressive behavior.