Mechanotransduction in cancer

•Tumor tissues stiffen in disease, but cancer cells can soften.•Some cancer cell types lose aspects of stiffness sensing.•Ras, FAK and PI3K/Akt signaling have been implicated in mechanotransduction.•New materials and devices reveal mechanisms of mechanotransduction in cancer. Tissue stiffness is tightly controlled under normal conditions, but changes with disease. In cancer, tumors often tend to be stiffer than the surrounding uninvolved tissue, yet the cells themselves soften. Within the past decade, and particularly in the last few years, there is increasing evidence that the stiffness of the extracellular matrix modulates cancer and stromal cell mechanics and function, influencing such disease hallmarks as angiogenesis, migration, and metastasis. This review briefly summarizes recent studies that investigate how cancer cells and fibrosis-relevant stromal cells respond to ECM stiffness, the possible sensing appendages and signaling mechanisms involved, and the emergence of novel substrates—including substrates with scar-like fractal heterogeneity—that mimic the in vivo mechanical environment of the cancer cell.