Syndecan-2 enhances invasive motility in colon cancer cells via a laminin-332-integrin α6β1 axis.

Syndecan-2 (SDC-2) is a key regulator of colon cancer progression, but its cooperation with integrins in cell motility is not fully understood. Here, we show that SDC-2 overexpression in HT29 colon cancer cells (HT29-S2W) enhances adhesion, spreading, and migration on laminin-332, an extracellular matrix component linked to poor prognosis. These effects correlate with increased basal membrane localization of integrin α6, as well as elevated expression and deposition of laminin-332 subunits (α3, β3, and γ2), thereby promoting laminin-332 assembly within the extracellular matrix. Proximity ligation assays revealed enhanced interactions between SDC-2 and integrin α6β1 following SDC-2 overexpression, indicating coordinated signaling mediated by laminin-332. Notably, HT29-S2W cells adhered more efficiently to full-length laminin-332 containing the SDC-2-binding LG4/5 modules of the laminin α3 chain than to truncated laminin-332 lacking these modules. Furthermore, both an anti-integrin α6 antibody and a laminin-α3-derived peptide (A3G75aR) significantly inhibited adhesion to full-length laminin-332. In metastatic DLD-1 cells, which express high levels of SDC-2 and laminin-332, combined treatment with the antibody and peptide markedly suppressed cell migration and invasion. Collectively, these findings identify an SDC-2-laminin-332-integrin α6β1 axis that drives invasive motility and may represent a promising therapeutic target in metastatic colorectal cancer.