title: Novel regulatory role of neuropilin-1 in endothelial-to-mesenchymal transition and fibrosis in pancreatic ductal adenocarcinoma.
abstract: Pancreatic ductal adenocarcinoma (PDAC) is characterized by an intense fibrotic reaction termed tumor desmoplasia, which is in part responsible for its aggressiveness. Endothelial cells have been shown to display cellular plasticity in the form of endothelial-to-mesenchymal transition (EndMT) that serves as an important source of fibroblasts in pathological disorders, including cancer. Angiogenic co-receptor, neuropilin-1 (NRP- 1) actively binds TGFβ1, the primary mediator of EndMT and is involved in oncogenic processes like epithelial-to-mesenchymal transition (EMT). NRP-1 and TGFβ1 signaling have been shown to be aberrantly up-regulated in PDAC. We report herein a positive correlation between NRP-1 levels, EndMT and fibrosis in human PDAC xenografts. Loss of NRP-1 in HUVECs limited TGFβ1-induced EndMT as demonstrated by gain of endothelial and loss of mesenchymal markers, while maintaining endothelial cell architecture. Knockdown of NRP-1 down-regulated TGFβ canonical signaling (pSMAD2) and associated pro-fibrotic genes. Overexpression of NRP-1 exacerbated TGFβ1-induced EndMT and up-regulated TGFβ signaling and expression of pro-fibrotic genes. In vivo, loss of NRP-1 attenuated tumor perfusion and size, accompanied by reduction in EndMT and fibrosis. This study defines a previously unrecognized role of NRP-1 in regulating TGFβ1-induced EndMT and fibrosis, and advocates NRP-1 as a therapeutic target to reduce tumor fibrosis and PDAC progression.
authors.affiliation: Division of Cardiology, Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Canada.|Institute of Medical Science, University of Toronto, Toronto, Canada.
authors.forename: Pratiek N
authors.initials: PN
authors.lastname: Matkar
authors.affiliation: Division of Vascular Surgery, Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Canada.|Division of Cardiac Surgery, Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Canada.|Institute of Medical Science, University of Toronto, Toronto, Canada.
authors.forename: Krishna Kumar
authors.initials: KK
authors.lastname: Singh
authors.affiliation: Division of Cardiology, Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Canada.
authors.forename: Dmitriy
authors.initials: D
authors.lastname: Rudenko
authors.affiliation: Division of Cardiology, Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Canada.
authors.forename: Yu Jin
authors.initials: YJ
authors.lastname: Kim
authors.affiliation: Division of Cardiology, Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Canada.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Kuliszewski
authors.affiliation: Division of Laboratory Medicine, Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Canada.
authors.forename: Gerald J
authors.initials: GJ
authors.lastname: Prud'homme
authors.affiliation: Division of Medical Oncology and Hematology, Ontario Cancer Institute, Campbell Family Cancer Research Institute, Princess Margaret Cancer Centre, Toronto, Canada.
authors.forename: David W
authors.initials: DW
authors.lastname: Hedley
authors.affiliation: Division of Cardiology, Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Canada.|Institute of Medical Science, University of Toronto, Toronto, Canada.
authors.forename: Howard
authors.initials: H
authors.lastname: Leong-Poi
mesh_terms: D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics* / Q000378:metabolism / Q000628:therapy; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D059248:Chemoradiotherapy; D004358:Drug Therapy; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D005260:Female; D005355:Fibrosis / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D039942:Neuropilin-1 / Q000235:genetics* / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000628:therapy; D034622:RNA Interference; D011923:Rats, Nude; D023041:Xenograft Model Antitumor Assays
chemical_list: D039942:Neuropilin-1
keywords: endothelial cell; endothelial-to-mesenchymal transition; fibrosis; neuropilin-1; pancreatic cancer