ArticleOncogene2017
Upregulation of RET induces perineurial invasion of pancreatic adenocarcinoma.
Article in Oncogene, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 39 papers.
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Who cites it
39 citing papers in PubMed, 51 citations in OpenAlex.
- Emerging Precision Therapeutic Strategies in Pancreatic Ductal Adenocarcinoma: KRAS Targeting, DDR Vulnerabilities, Immune Redirection, and Tumor Microenvironment Remodeling.Pharmaceutics · 2026Review
- Pathophysiology, assessment, and treatment of pain in patients with pancreatic ductal adenocarcinoma.Journal of gastroenterology · 2026Article
- Heterocellular crosstalk and architecture of the pancreatic tumour microenvironment.Nature reviews. Cancer · 2026Review
- Review
- Peripheral Nerve-Cancer Interactions in the Tumor Microenvironment: A Three-Dimensional Framework Integrating Mechanisms, Modulators, and Therapeutic Strategies.Research (Washington, D.C.) · 2026Review
- Blockade of CC chemokine receptor 2 suppresses pancreatic cancer progression through the interaction with macrophages in the tumor microenvironment.Scientific reports · 2025Article
- Targeting the peripheral neural-tumour microenvironment for cancer therapy.Nature reviews. Drug discovery · 2024Review
- Targeting the RET tyrosine kinase in neuroblastoma: A review and application of a novel selective drug design strategy.Biochemical pharmacology · 2023Review
- Article
- Pancreatic Ductal Adenocarcinoma Induces Neural Injury that Promotes a Transcriptomic and Functional Repair Signature by Peripheral Neuroglia.Research square · 2023Article
- Important Cells and Factors from Tumor Microenvironment Participated in Perineural Invasion.Cancers · 2023Review
- Peak density of immature nerve cells occurs with high-grade dysplasia in intraductal papillary mucinous neoplasms of the pancreas.The Journal of pathology · 2022Article
- The Role of Extracellular Vesicles in Cancer-Nerve Crosstalk of the Peripheral Nervous System.Cells · 2022Review
- High‑glucose microenvironment promotes perineural invasion of pancreatic cancer via activation of hypoxia inducible factor 1α.Oncology reports · 2022Article
- Schwann Cells in Digestive System Disorders.Cells · 2022Review
- RET signaling pathway and RET inhibitors in human cancer.Frontiers in oncology · 2022Review
- Sporadic Medullary Thyroid Carcinoma: Towards a Precision Medicine.Frontiers in endocrinology · 2022Review
- Hallmarks of RET and Co-occuring Genomic Alterations inMolecular cancer therapeutics · 2021Review
- Targeting Rearranged during Transfection in Cancer: A Perspective on Small-Molecule Inhibitors and Their Clinical Development.Journal of medicinal chemistry · 2021Review
- Intraductal carcinoma of the salivary gland with NCOA4-RET: expanding the morphologic spectrum and an algorithmic diagnostic approach.Human pathology · 2021Article
Corrections and comments
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Authors and funding
9 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.