The Galectin-3-binding protein promotes angiogenesis in pancreatic cancer via simultaneous upregulation of VEGFA and direct HUVEC activation mediated by and VAMP5-STAT3

Abstract Pancreatic ductal adenocarcinoma (PDAC) is ranked by the lowest 5-year survival rate worldwide. Given the lack of early symptoms and diagnostic biomarkers, most patients present with either local or distant metastasis at diagnosis. We previously demonstrated that Galectin-3-binding protein (Gal-3BP) is overexpressed in PDAC cells and promotes metastasis through the EGFR pathway, using proteomic analysis of PDAC tumor interstitial fluid (TIF). In the present study, we show the Gal-3BP promotes angiogenesis in PDAC by vascular endothelial growth factor A (VEGFA) upregulation via STAT3 activation. Furthermore, we reveal the Gal-3BP directly promotes migration and tube formation of vascular endothelial cells through STAT3 phosphorylation, mediated not by a VEGF receptor but by VAMP5. To explore the clinical application of these findings, we developed a humanized, high-affinity Gal-3BP antibody to block the dual angiogenic function of Gal-3BP. The #132 clone of the Gal-3BP antibody significantly reduced blood vessel density in PDAC orthotopic tumors and attenuated PDAC metastasis in a lung metastasis model. Therefore, we demonstrate the antibody-mediated blockade of Gal-3BP attenuates the angiogenesis in PDAC and propose it as a novel therapeutic strategy.