Upregulation of RET induces perineurial invasion of pancreatic adenocarcinoma

M. Amit, S. Na'Ara, L. Leider-Trejo, Y. Binenbaum, N. Kulish, E. Fridman, A. Shabtai-Orbach, R. J. Wong, Z. Gil

Research output: Contribution to journalArticle

23 Scopus citations

Abstract

Tumor spread along nerves, a phenomenon known as perineurial invasion, is common in various cancers including pancreatic ductal adenocarcinoma (PDAC). Neural invasion is associated with poor outcome, yet its mechanism remains unclear. Using the transgenic Pdx-1-Cre/KrasG12D/p53R172H (KPC) mouse model, we investigated the mechanism of neural invasion in PDAC. To detect tissue-specific factors that influence neural invasion by cancer cells, we characterized the perineurial microenvironment using a series of bone marrow transplantation (BMT) experiments in transgenic mice expressing single mutations in the Cx3cr1, GDNF and CCR2 genes. Immunolabeling of tumors in KPC mice of different ages and analysis of human cancer specimens revealed that RET expression is upregulated during PDAC tumorigenesis. BMT experiments revealed that BM-derived macrophages expressing the RET ligand GDNF are highly abundant around nerves invaded by cancer. Inhibition of perineurial macrophage recruitment, using the CSF-1R antagonist GW2580 or BMT from CCR2-deficient donors, reduced perineurial invasion. Deletion of GDNF expression by perineurial macrophages, or inhibition of RET with shRNA or a small-molecule inhibitor, reduced perineurial invasion in KPC mice with PDAC. Taken together, our findings show that RET is upregulated during pancreas tumorigenesis and its activation induces cancer perineurial invasion. Trafficking of BM-derived macrophages to the perineurial microenvironment and secretion of GDNF are essential for pancreatic cancer neural spread.

Original languageEnglish (US)
Pages (from-to)3232-3239
Number of pages8
JournalOncogene
Volume36
Issue number23
DOIs
StatePublished - Jun 8 2017

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

Fingerprint Dive into the research topics of 'Upregulation of RET induces perineurial invasion of pancreatic adenocarcinoma'. Together they form a unique fingerprint.

Cite this