Pancreatic ductal adenocarcinoma (PDAC), the most common type of pancreatic cancer, is a prominent cause of cancer mortality in Canada, with the lowest five-year survival rate. Recent evidence suggests that cellular processes such as endothelial-to-mesenchymal transition (EndMT), epithelial-to-mesenchymal transition (EMT), and autophagy when aberrantly upregulated, are unifying mechanisms of chemoresistance in PDAC. Apart from being involved in numerous cancer-initiating and promoting events, angiogenic co-receptor neuropilin-1 (NRP-1) is a mediator of TGFβ signaling, which remains the primary signaling mechanism regulating EndMT, EMT and autophagy. Overexpression of NRP-1 and transforming growth factor β (TGFβ) signaling is well-documented in PDAC. We investigated the role of NRP-1 in regulating EndMT, EMT and autophagy in pancreatic cancer. We observed a significant association between NRP-1 levels, EndMT, EMT and autophagy markers’ expression in human PDAC tissue obtained from a clinically relevant orthotopic model of PDAC in athymic rats. Knockdown of NRP-1 inhibited, while overexpression of NRP-1 promoted EndMT and associated fibrosis, respectively, through modulation of TGFβ signaling and Slug expression in endothelial cells. Moreover, in human pancreatic cancer cell lines and their chemoresistant forms, knockdown of NRP-1 inhibited, while overexpression of NRP-1 promoted EMT and associated invasiveness, respectively, via modulation of TGFβ signaling and SNAIL expression. Finally, NRP-1 knockdown inhibited autophagy, while NRP-1 overexpression activated autophagy by repressing mTOR activation in human pancreatic cancer cell lines. NRP-1 was also able to regulate autophagy induced by nutrient starvation and chemotherapy stress and subsequently, affect cancer cell survival. Together, these results suggest that anti-NRP-1 therapy could potentially overcome chemoresistance in PDAC and may emerge as an adjuvant therapy to existing chemotherapy strategies.Ph.D
