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.

VEGF-A/Neuropilin 1 Pathway Confers Cancer Stemness via Activating Wnt/β-Catenin Axis in Breast Cancer Cells

“…NRP-1 is an angiogenic co-receptor of VEGF-A, and involved in epithelial-to-mesenchymal transition (EMT) in pancreatic ductal adenocarcinoma [4]. Additionally, VEGF-A could enhance epidermal cancer stem cell survival, and the formation of aggressive and highly vascularized tumors via NRP-1 [5, 6].…”

“…VEGF-A/NRP-1 axis could facilitate breast cancer progression via facilitating EMT [7]. Notably, EMT could enable tumor cells with stemness characteristics [8]. Furthermore, our previous study has indicated that knockdown of NRP-1 could inhibit cell proliferation, and promote cell apoptosis in breast cancer cells [9].…”

Jack of many trades: Multifaceted role of neuropilins in pancreatic cancer

“…If successful, EndMT inhibition may lead to improved drug delivery or delayed PDAC tumor progression due to restricted CAF recruitment. However, the effects of treatment on survival in vivo and the elucidation of a complete mechanistic signaling pathway remain unknown and warrant further investigation …”

“…overlap with several other cellular functions. The TGF ‐β canonical signaling pathway mainly yields antiproliferative, cell transformative, and immunosuppressive effects, which can be inhibited through TGF ‐β noncanonical signaling . NRP s activate p130Cas adaptor molecule upon binding to GF s and can inhibit canonical SMAD 2/3 signaling, while preferring noncanonical signaling.…”

“…The TGF-β canonical signaling pathway mainly yields antiproliferative, cell transformative, and immunosuppressive effects, which can be inhibited through TGF-β noncanonical signaling. 16,65 NRPs activate p130Cas adaptor molecule upon binding to GFs and can inhibit canonical SMAD2/3 signaling, while preferring noncanonical signaling. Additionally, SEMA3 ligands crosstalk with NRPs and plexins in order to regulate axonal guidance and suppress other cellular functions such as proliferation, migration, and angiogenesis 16 delivery due to the extracellular matrix and high interstitial pressure within the tumors.…”