Upregulation of RET induces perineurial invasion of pancreatic adenocarcinoma

• Published in: Oncogene 2017-06, Vol.36 (23), p.3232-3239
• Main Authors: Amit, M, Na'ara, S, Leider-Trejo, L, Binenbaum, Y, Kulish, N, Fridman, E, Shabtai-Orbach, A, Wong, R J, Gil, Z
• Format: Article
• Language: English
• Subjects: 13; 13/1; 13/109; 13/31; 13/89; 42/34; 59; 631/67/327; 631/67/395; Adenocarcinoma; Adenocarcinoma - genetics; Adenocarcinoma - metabolism; Adenocarcinoma - pathology; Animals; Apoptosis; Bone marrow transplantation; Cancer; Cancer metastasis; Carcinoma, Pancreatic Ductal - genetics; Carcinoma, Pancreatic Ductal - metabolism; Carcinoma, Pancreatic Ductal - pathology; Care and treatment; CCR2 protein; Cell Biology; Cell Proliferation; Cerebrospinal fluid; Complications and side effects; CX3CR1 protein; Development and progression; Female; Gene expression; Genetic aspects; Glial cell line-derived neurotrophic factor; Health aspects; Human Genetics; Humans; Internal Medicine; Lymphocytes; Macrophages; Macrophages - metabolism; Macrophages - pathology; Medical prognosis; Medical research; Medicine; Medicine & Public Health; Metastasis; Mice; Mice, Inbred C57BL; Microenvironments; Monocyte chemoattractant protein 1; Mutation; Neoplasm Invasiveness; Nerves; Nervous System - metabolism; Nervous System - pathology; Oncogenes; Oncology; original-article; Otolaryngology; Pancreatic cancer; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - pathology; Peripheral nervous system diseases; Proto-Oncogene Proteins c-ret - genetics; Proto-Oncogene Proteins c-ret - metabolism; Research centers; Surgery; Transgenic animals; Transgenic mice; Tumor Cells, Cultured; Tumorigenesis
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2016.483

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.