Abstract The extracellular matrix (ECM) has been demonstrated to be dysregulated and crucial for malignant progression in gastric cancer (GC), but the mechanism is not well understood. Here, that discoidin domain receptor 1 (DDR1), a principal ECM receptor, is recognized as a key driver of GC progression is reported. Mechanistically, DDR1 directly interacts with the PAS domain of hypoxia‐inducible factor‐1α (HIF‐1α), suppresses its ubiquitination and subsequently strengthens its transcriptional regulation of angiogenesis. Additionally, DDR1 upregulation in GC cells promotes actin cytoskeleton reorganization by activating HIF‐1α/ Ras Homolog Family Member A (RhoA)/Rho‐associated protein kinase 1 (ROCK1) signaling, which in turn enhances the metastatic capacity. Pharmacological inhibition of DDR1 suppresses GC progression and angiogenesis in patient‐derived xenograft (PDX) and organoid models. Taken together, this work first indicates the effects of the DDR1‐HIF‐1α axis on GC progression and reveals the related mechanisms, providing experimental evidence for DDR1 as a therapeutic target for GC.

DDR1 Drives Malignant Progression of Gastric Cancer by Suppressing HIF‐1α Ubiquitination and Degradation