Initiation of fibronectin fibrillogenesis is an enzyme-dependent process

Fibronectin fibrillogenesis and mechanosensing both depend on integrin-mediated force transmission to the extracellular-matrix. However, force transmission is in itself dependent on fibrillogenesis, and fibronectin fibrils are found in soft embryos where high forces cannot be applied, suggesting that force cannot be the sole initiator of fibrillogenesis. Here we identify a novel nucleation step prior to force transmission, driven by fibronectin oxidation mediated by lysyl-oxidase enzyme family members. This oxidation induces fibronectin clustering that promotes early adhesion, alters cellular response to soft matrices, and enhances force transmission to the matrix. In contrast, absence of fibronectin oxidation abrogates fibrillogenesis, perturbs cell-matrix adhesion, and compromises mechanosensation. Moreover, fibronectin oxidation promotes cancer cells colony formation in soft agar as well as collective and single-cell migration. These results reveal a yet unidentified, force-independent enzyme-dependent mechanism that initiates fibronectin fibrillogenesis, establishing a critical step in cell adhesion and mechanosensing.