title: Upregulation of RET induces perineurial invasion of pancreatic adenocarcinoma.
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.
authors.affiliation: Head and Neck Surgery Department, MD Anderson Cancer Center University of Texas, Houston, TX, USA.|The Laboratory for Applied Cancer Research, Clinical Research Institute at Rambam, Rappaport Institute of Medicine and Research, The Technion, Israel Institute of Technology, Haifa, Israel.|Department of Otolaryngology Head and Neck Surgery, The Head and Neck Center, Rambam Healthcare Campus, Clinical Research Institute at Rambam, Rappaport Institute of Medicine and Research, Rambam Medical Center, The Technion, Israel Institute of Technology, Haifa, Israel.
authors.forename: M
authors.initials: M
authors.lastname: Amit
authors.affiliation: The Laboratory for Applied Cancer Research, Clinical Research Institute at Rambam, Rappaport Institute of Medicine and Research, The Technion, Israel Institute of Technology, Haifa, Israel.|Department of Otolaryngology Head and Neck Surgery, The Head and Neck Center, Rambam Healthcare Campus, Clinical Research Institute at Rambam, Rappaport Institute of Medicine and Research, Rambam Medical Center, The Technion, Israel Institute of Technology, Haifa, Israel.
authors.forename: S
authors.initials: S
authors.lastname: Na'ara
authors.affiliation: Department of Pathology, Tel Aviv Medical Center, Tel Aviv, Israel.
authors.forename: L
authors.initials: L
authors.lastname: Leider-Trejo
authors.affiliation: The Laboratory for Applied Cancer Research, Clinical Research Institute at Rambam, Rappaport Institute of Medicine and Research, The Technion, Israel Institute of Technology, Haifa, Israel.
authors.forename: Y
authors.initials: Y
authors.lastname: Binenbaum
authors.affiliation: The Laboratory for Applied Cancer Research, Clinical Research Institute at Rambam, Rappaport Institute of Medicine and Research, The Technion, Israel Institute of Technology, Haifa, Israel.
authors.forename: N
authors.initials: N
authors.lastname: Kulish
authors.affiliation: The Laboratory for Applied Cancer Research, Clinical Research Institute at Rambam, Rappaport Institute of Medicine and Research, The Technion, Israel Institute of Technology, Haifa, Israel.|Department of Otolaryngology Head and Neck Surgery, The Head and Neck Center, Rambam Healthcare Campus, Clinical Research Institute at Rambam, Rappaport Institute of Medicine and Research, Rambam Medical Center, The Technion, Israel Institute of Technology, Haifa, Israel.
authors.forename: E
authors.initials: E
authors.lastname: Fridman
authors.affiliation: The Laboratory for Applied Cancer Research, Clinical Research Institute at Rambam, Rappaport Institute of Medicine and Research, The Technion, Israel Institute of Technology, Haifa, Israel.
authors.forename: A
authors.initials: A
authors.lastname: Shabtai-Orbach
authors.affiliation: Department of Surgery Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: R J
authors.initials: RJ
authors.lastname: Wong
authors.affiliation: The Laboratory for Applied Cancer Research, Clinical Research Institute at Rambam, Rappaport Institute of Medicine and Research, The Technion, Israel Institute of Technology, Haifa, Israel.|Department of Otolaryngology Head and Neck Surgery, The Head and Neck Center, Rambam Healthcare Campus, Clinical Research Institute at Rambam, Rappaport Institute of Medicine and Research, Rambam Medical Center, The Technion, Israel Institute of Technology, Haifa, Israel.
authors.forename: Z
authors.initials: Z
authors.lastname: Gil
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D017209:Apoptosis; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation; D005260:Female; D006801:Humans; D008264:Macrophages / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009361:Neoplasm Invasiveness; D009420:Nervous System / Q000378:metabolism / Q000473:pathology*; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human