A novel association of neuropilin-1 and MUC1 in pancreatic ductal adenocarcinoma: role in induction of VEGF signaling and angiogenesis.

Abstract

We report that MUC1, a transmembrane glycoprotein that is overexpressed in >80% of pancreatic ductal adenocarcinoma (PDA) induced a pro-angiogenic tumor microenvironment by increasing the levels of neuropilin-1 (NRP1, a co-receptor of VEGF) and its ligand, VEGF. Expression of tumor-associated MUC1 (tMUC1) positively correlated with NRP1 levels in human and mouse PDA. Further, tMUC1hi PDA cells secreted high levels of VEGF and expressed high levels of VEGF receptor 2 and its phosphorylated forms as compared to tMUC1low/null PDA. This enabled the tMUC1hi/NRP1hi PDA cells to a) induce endothelial cell tube formation, b) generate long ectopic blood vessels and c) enhance distant metastasis in a zebrafish xenograft model. Concurrently, the proteins associated with epithelial to mesenchymal transition, N-cadherin and Vimentin, were highly induced in these tMUC1/NRP1hi PDA cells. Hence, blocking signaling via the NRP1-VEGF axis significantly reduced tube formation, new vessel generation, and metastasis induced by tMUC1hi PDA cells. Finally, we show that blocking the interaction between VEGF165 and NRP1 with a NRP1 antagonist significantly reduced VEGFR signaling and PDA tumor growth in vivo. Taken together, our data suggests a novel molecular mechanism by which tMUC1 may modulate NRP1-dependent VEGFR signaling in PDA cells.