Integrin α₆ and EGFR signaling converge at mechanosensitive calpain 2

Cells sense and respond to mechanical cues from the extracellular matrix (ECM) via integrins. ECM stiffness is known to enhance integrin clustering and response to epidermal growth factor (EGF), but we lack information on when or if these mechanosensitive growth factor receptors and integrins converge intracellularly. Towards closing this knowledge gap, we combined a biomaterial platform with transcriptomics, molecular biology, and functional assays to link integrin-mediated mechanosensing and epidermal growth factor receptor (EGFR) signaling. We found that high integrin α₆ expression controlled breast cancer cell adhesion and motility on soft, laminin-coated substrates, and this mimicked the response of cells to EGF stimulation. The mechanisms that drove both mechanosensitive cell adhesion and motility converged on calpain 2, an intracellular protease important for talin cleavage and focal adhesion turnover. EGF stimulation enhanced adhesion and motility on soft substrates, but required integrin α₆ and calpain 2 signaling. In sum, we identified a new role for integrin α₆ mechanosensing in breast cancer, wherein cell adhesion to laminin on soft substrates mimicked EGF stimulation. We identified calpain 2, downstream of both integrin α₆ engagement and EGFR phosphorylation, as a common intracellular signaling node, and implicate integrin α₆ and calpain 2 as potential targets to inhibit the migration of cancer cells in stiff tumor environments.