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ZFIN ID: ZDB-PUB-160126-12
A novel association of neuropilin-1 and MUC1 in pancreatic ductal adenocarcinoma: role in induction of VEGF signaling and angiogenesis
Zhou, R., Curry, J.M., Roy, L.D., Grover, P., Haider, J., Moore, L.J., Wu, S.T., Kamesh, A., Yazdanifar, M., Ahrens, W.A., Leung, T., Mukherjee, P.
Date: 2016
Source: Oncogene 35(43): 5608-5618 (Journal)
Registered Authors: Leung, Tin Chung
Keywords: none
MeSH Terms:
  • Animals
  • Carcinoma, Pancreatic Ductal/genetics
  • Carcinoma, Pancreatic Ductal/metabolism*
  • Carcinoma, Pancreatic Ductal/pathology*
  • Cell Line, Tumor
  • Disease Models, Animal
  • Endothelial Cells/metabolism
  • Epithelial-Mesenchymal Transition
  • Gene Expression
  • Heterografts
  • Humans
  • Mice
  • Mice, Knockout
  • Mucin-1/genetics
  • Mucin-1/metabolism*
  • Neoplasm Metastasis
  • Neovascularization, Pathologic/metabolism
  • Neuropilin-1/genetics
  • Neuropilin-1/metabolism*
  • Pancreatic Neoplasms/genetics
  • Pancreatic Neoplasms/metabolism*
  • Pancreatic Neoplasms/pathology*
  • Receptors, Vascular Endothelial Growth Factor/genetics
  • Receptors, Vascular Endothelial Growth Factor/metabolism
  • Signal Transduction
  • Vascular Endothelial Growth Factor A/metabolism
  • Zebrafish
PubMed: 26804176 Full text @ Oncogene
We report that Mucin1 (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 vascular endothelial growth factor (VEGF)) and its ligand VEGF. Expression of tumor-associated MUC1 (tMUC1) positively correlated with NRP1 levels in human and mouse PDA. Further, tMUC1(hi) PDA cells secreted high levels of VEGF and expressed high levels of VEGF receptor 2 (VEGFR2) and its phosphorylated forms as compared with tMUC1(low/null) PDA. This enabled the tMUC1(hi)/NRP1(hi) 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/NRP1(hi) PDA cells. Hence, blocking signaling via the NRP1-VEGF axis significantly reduced tube formation, new vessel generation and metastasis induced by tMUC1(hi) 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 suggest a novel molecular mechanism by which tMUC1 may modulate NRP1-dependent VEGFR signaling in PDA cells.