Extracellular matrix stiffness drives cutaneous squamous cell carcinoma malignant progression via YAP-dependent glycolysis

The extracellular matrix (ECM) stiffness is significantly elevated in cutaneous squamous cell carcinoma (cSCC) and positively correlates with Clark level, tumor thickness and poor disease-free survival, implicating ECM stiffness as a driver of cSCC malignant progression. Using clinical samples, hydrogels of different stiffness, and a mouse xenograft model, we demonstrated that ECM stiffening activates the integrin-FAK-YAP mechanotransduction pathway. This activation promotes YAP nuclear translocation and YAP-TEAD1 complex formation, which in turn enhances the transcription of the glycolytic enzyme PKM2. Consequently, PKM2 upregulation drives aerobic glycolysis in cSCC cells, leading to increased proliferation, migration, apoptosis resistance, and EMT progression. Therapeutic inhibition of ECM stiffness, YAP transcriptional activity or glycolysis markedly reduces tumor growth and malignant behaviors in vivo. These findings identify a critical mechano-metabolic signaling cascade driving cSCC malignant progression, providing novel targets for therapeutic intervention against cancers associated with fibrosis and mechanical stress.