Novel regulatory role of neuropilin-1 in endothelial-to-mesenchymal transition and fibrosis in pancreatic ductal adenocarcinoma

Howard Leong-Poi,Yu Jin Kim,Dmitriy Rudenko,Pratiek N. Matkar,Krishna Kumar Singh,Michael A. Kuliszewski,David W. Hedley,Gerald J. Prud’homme

doi:10.18632/oncotarget.11060

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.

Highlights

Despite improvements in our understanding of cancer biology and advances in cancer therapies, malignant tumors remain a leading cause of morbidity and mortality [1,2,3]
Pancreatic ductal adenocarcinoma (PDAC) is characterized by an intense fibrotic reaction termed tumor desmoplasia, which is in part responsible for its aggressiveness
PDAC is composed of epithelial cells with variable degrees of ductal differentiation, surrounded by an intense fibrotic reaction called tumor desmoplasia, often referred to as tumor stroma/fibrosis [14,15,16,17,18]

Summary

Introduction

Despite improvements in our understanding of cancer biology and advances in cancer therapies, malignant tumors remain a leading cause of morbidity and mortality [1,2,3]. The advancement of novel therapeutic strategies that target the underlying biological processes involved in pancreatic cancer growth and metastases remains important [7]. Less vascularized tumors like PDAC, remain largely incurable despite the significant advances in anti-angiogenesis research [12, 13]. Cancerassociated fibroblasts (CAFs) along with other stromal cells constitute the majority of the PDAC tumor [19, 20]. Approved therapies targeting desmoplasia/fibrosis [26,27,28] opens new avenues for discovering novel strategies to suppress desmoplasia

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Conclusion