Introduction: Cancer cells integrate biochemical and mechanical cues from the tumour microenvironment to regulate cellular phenotype, invasiveness, and therapy response. Heparan sulfate proteoglycans (HSPGs) are central mediators of extracellular signalling; however, their role in mechanotransduction in ovarian cancer remains poorly understood. We investigated how dysregulated heparan sulfate (HS) biosynthesis driven by exostosin glycosyltransferase 1 (EXT1) influences mechanical signal transduction and therapeutic vulnerability in ovarian cancer.
Methods: EXT1 expression was assessed in ovarian cancer tissues and cell lines and correlated with clinical outcome. Mechanosensitive responses were evaluated using polydimethylsiloxane (PDMS) substrates with tunable Young’s modulus. Cell migration, invasion, and epithelial–mesenchymal transition (EMT) markers were analysed following EXT1 overexpression or silencing. Activation of mechanotransduction pathways, including Rho-dependent cytoskeletal remodelling, focal adhesion kinase (FAK), and TGFβ signalling, was assessed biochemically. Therapeutic responses were evaluated using enzymatic HS degradation (heparinase), pharmacological inhibition of FAK and TGFβ receptor I, and platinum-based chemotherapy.
Results: EXT1 was selectively upregulated in aggressive ovarian tumours and cell lines, correlating with reduced progression-free survival and enhanced EMT. EXT1 overexpression increased cellular sensitivity to matrix stiffness, promoting migration, invasion, and activation of Rho, FAK, and TGFβ signalling pathways. In contrast, EXT1 silencing attenuated mechanotransduction signalling and partially reversed mesenchymal traits. Combined inhibition of HS and blockade of FAK and TGFβ receptor I synergistically suppressed aggressive phenotypes and enhanced sensitivity to platinum-based chemotherapy.
Conclusions: These findings identify EXT1-dependent HS remodelling as a critical regulator of mechanotransduction in ovarian cancer and suggest that targeting HS-mediated mechanical signalling may improve therapeutic efficacy.
