VSTM2L mediates the release of extracellular vimentin to drive lymph node metastasis in gastric cancer

Lymph node metastasis (LNM), the most common route of gastric cancer (GC) dissemination, remains poorly understood. This study aimed to elucidate the role of V-Set and Transmembrane Domain Containing 2 Like (VSTM2L) in GC LNM. VSTM2L expression was evaluated by immunohistochemistry, qPCR, and western blot. Its effects on cell proliferation, invasion, lymphangiogenesis, and metastasis were examined via colony formation, Transwell, tube formation, and in vivo experiments, respectively. Protein interactions were analyzed by immunoprecipitation and GST-pull down. The role of VSTM2L in promoting vimentin secretion was assessed using Ponceau Red staining and Enzyme-Linked Immunosorbent Assay (ELISA). Rescue experiments were conducted to confirm the functional significance of vimentin. VSTM2L was significantly upregulated in GC cell lines and lymph node-positive tissues, and its high expression correlated with poor survival. Loss- and gain-of-function experiments demonstrated that VSTM2L promotes GC cell proliferation, invasion, and lymphangiogenesis. Mechanistically, VSTM2L interacted with vimentin to enhance its intracellular stability and promote its extracellular secretion. The released vimentin subsequently upregulated focal adhesion complex proteins intracellularly and activated Vascular Endothelial Growth Factor Receptor-3 (VEGFR-3) signaling in human lymphatic endothelial cells, leading to cytoskeletal rearrangement and lymphangiogenesis, respectively. Consistent with this mechanism, both in vitro and in vivo evidence confirmed that the secretion of vimentin is essential for the pro-lymphangiogenic effects of VSTM2L. We identify VSTM2L as a novel and potent driver of LNM. Our findings highlight the therapeutic potential of targeting the VSTM2L-extracellular vimentin axis in GC and elucidate a previously unrecognized mechanism driving vimentin secretion and lymphatic metastasis.