Discoidin domain receptor 1 contributes to colorectal cancer progression by promoting cell migration and invasion

Colorectal cancer (CRC) progression is strongly influenced by interactions between tumor cells and the collagen-rich extracellular matrix. Discoidin domain receptor 1 (DDR1), a collagen-activated receptor tyrosine kinase, has been associated with poor prognosis in several epithelial malignancies, including CRC. However, the mechanisms by which DDR1 contributes to metastatic initiation remain incompletely understood. Here, we investigated the role of DDR1 in regulating CRC cell migration and invasion within type I collagen-rich microenvironments. DDR1 overexpression in low-invasive HT-29 cells was sufficient to enhance collective spheroid migration on collagen. Conversely, pharmacological inhibition or genetic silencing of DDR1 in highly invasive HCT-116 cells significantly impaired two-dimensional and three-dimensional migration as well as invasion within fibrillar collagen matrices. Mechanistically, DDR1 inactivation restored epithelial features, as evidenced by increased membrane localization of E-cadherin, decreased N-cadherin expression and reduced MT1-MMP expression. These findings indicate that DDR1 promotes invasion through coordinated regulation of epithelial adhesion and localized collagen remodeling rather than global extracellular matrix degradation. Phosphoproteomic profiling further suggested that DDR1 activates a non-canonical pro-migratory signaling network independent of AKT and Wnt/β-catenin pathways, involving modulation of GSK-3, WNK1, and RSK signaling. Collectively, our results identify DDR1 as a critical regulator of collagen-dependent migration and invasion in CRC and highlight its kinase activity as a potential therapeutic target to limit metastatic progression.