Matrix stiffness mechanically conditions EMT and migratory behavior of oral squamous cell carcinoma

Abstract

Tumors are composed of heterogeneous phenotypes, each having different sensitivities to the microenvironment. One microenvironment characteristic–matrix stiffness–helps regulate malignant transformation and invasion in mammary tumors, but its influence on oral squamous cell carcinoma (OSCC) is unclear. We observed that on stiff matrices, a highly invasive OSCC line with low E-cad/N-cad ratio (InvH/E:NL; SCC25) had increased migration velocity and decreased adhesion strength compared to a poorly invasive OSCC line with high E-cad/N-cad ratio (InvL/E:NH; Cal27). However, InvL/E:NH cells acquire a mesenchymal signature and begin to migrate faster when exposed to prolonged time on a stiff niche, suggesting that cells could be mechanically conditioned. InvL/E:NH cells migrated faster due to increased focal adhesion assembly, which could be reduced when increasing integrin affinity with high divalent cation concentrations. Mirroring these data in human patients, we observed that collagen organization, an indicator of matrix stiffness, was increased with advanced disease and correlated with early recurrence. Consistent with epithelial tumors, our data suggests that OSCC cells are mechanically sensitive and that their contribution to tumor progression is mediated in part by this sensitivity.