Figure 5. Mechanotransduction in cancer cells.

Schematic representation of how increased extracellular matrix (ECM) stiffness and altered cytoskeletal tension can contribute to tumour formation. Increased ECM stiffness may arise from fibrosis, or in response to increased cytoskeletal tension, caused for examples by oncogene (Ras)-driven ERK activation. The increased ECM stiffness is sensed by focal adhesions and activates integrins and focal adhesion kinase, thereby promoting focal adhesion assembly and stimulating the Rho-ROCK pathway. ROCK activation increases cytoskeletal tension by increasing myosin light chain (MLP) phosphorylation, which could result in further increases in ECM stiffness due to cellular mechanotransduction signalling, completing a self-enforcing (i.e., positive) feedback loop. Cross-talk between the Rho-ROCK pathway and the epidermal growth-factor receptor (EGFR)-Ras-ERK pathway, as well as modulation of Growth factor-dependent ERK activation by integrins, results in increased proliferation. ERK activation can also increase cytoskeletal tension through ROCK, further complementing the cross-talk between cytoskeletal tension and proliferative pathways. In breast cancer cells, the combined action of increased contractility and proliferation, triggered by increased extracellular matrix stiffness, may drive the undifferentiated and proliferative phenotype of mammary epithelial cancer cells and result in tumour formation. Decreasing Rho-mediated cytoskeletal contractility or ERK activity is sufficient to revert EGFR-transformed cells that form disorganized and invasive colonies into phenotypically normal cells that form polarized and growth-arrested acini in 3D culture ². Figure modified with permission from Ref. (58).