Ligand- and integrin-independent mechano-sensitive EGFR activation in lung cancer cells

Epidermal growth factor receptor (EGFR) is a transmembrane receptor tyrosine kinase that plays important roles in cell proliferation, differentiation and migration. EGFR overexpression or mutation is a hallmark of some cancers, leading to hyperactivation of downstream signalling. Co-regulation between EGF-dependent EGFR signalling and extracellular matrix (ECM) adhesion occurs in both healthy and malignant cells. Increasing ECM stiffness can contribute to lung cancer progression and is sensed by integrins to promote proliferation and invasion. Emerging evidence suggests non-canonical roles for EGFR in mechano-sensing, but the molecular mechanisms and functional consequences remain unclear. Here, we demonstrate that EGFR is activated in human lung cancer cells upon early adhesion to ECM substrates with physiologically relevant stiffness (28 kPa versus 1.5 kPa), independently of canonical ligands and integrins. Mechano-induced EGFR activation correlates with and requires active Src and F-actin, and it is coupled to stiffness-dependent plasma membrane retention of EGFR within disordered lipid microdomains. Early stiffness-dependent EGFR activation is required for enhanced migration. These findings uncover a non-canonical role for EGFR in early adhesion related mechano-sensing with potential implications for treatment of lung cancer.