MST1R kinase accelerates pancreatic cancer progression via effects on both epithelial cells and macrophages
| Autor: | Chih-Min Tang, Phillippe Foubert, Evangeline Mose, Andrew M. Lowy, Dawn Jaquish, Michele L. Babicky, Megan M. Harper, Alex Cazes, Michael C. Schmid, Karen Messer, Patrick Holman, Randall French, Jaclyn Miyamoto, Susan E. Waltz, Judith A. Varner, Zakkary J Walterscheid, Jeffery Chakedis, Nissi Varki, Hakan Alakus, Betzaira G. Childers, Jason K. Sicklick |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Male
0301 basic medicine Cancer Research pancreatic cancer Pancreatic Intraepithelial Neoplasia Inbred C57BL medicine.disease_cause Transgenic Mice 0302 clinical medicine Tumor Microenvironment 2.1 Biological and endogenous factors Aetiology Cancer Kinase Intracellular Signaling Peptides and Proteins Protein-Serine-Threonine Kinases 3. Good health Pancreatic Ductal 5.1 Pharmaceuticals Gene Knockdown Techniques 030220 oncology & carcinogenesis Disease Progression Female KRAS Development of treatments and therapeutic interventions Signal transduction Carcinoma Pancreatic Ductal Signal Transduction Clinical Sciences Oncology and Carcinogenesis Mst1r Macrophage polarization Mice Transgenic macrophage Protein Serine-Threonine Kinases Biology Proof of Concept Study Article Pancreatic Cancer 03 medical and health sciences Rare Diseases Pancreatic cancer Genetics medicine Animals Humans Oncology & Carcinogenesis Molecular Biology Tumor microenvironment Macrophages Carcinoma MST1R Receptor Protein-Tyrosine Kinases Epithelial Cells medicine.disease Mice Inbred C57BL Pancreatic Neoplasms 030104 developmental biology Cancer research MST1 Digestive Diseases |
| Zdroj: | ONCOGENE Oncogene, vol 38, iss 28 Oncogene |
| Popis: | The MST1R (RON) kinase is overexpressed in >80% of human pancreatic cancers, but its role in pancreatic carcinogenesis is unknown. In this study, we examined the relevance of Mst1r kinase to Kras driven pancreatic carcinogenesis using genetically engineered mouse models. In the setting of mutant Kras, Mst1r overexpression increased acinar-ductal metaplasia (ADM), accelerated the progression of pancreatic intraepithelial neoplasia (PanIN), and resulted in the accumulation of (mannose receptor C type 1) MRC1+, (arginase 1) Arg+ macrophages in the tumor microenvironment. Conversely, absence of a functional Mst1r kinase slowed PanIN initiation, resulted in smaller tumors, prolonged survival and a reduced tumor-associated macrophage content. Mst1r expression was associated with increased production of its ligand Mst1, and in orthotopic models, suppression of Mst1 expression resulted in reduced tumor size, changes in macrophage polarization and enhanced T cell infiltration. This study demonstrates the functional significance of Mst1r during pancreatic cancer initiation and progression. Further, it provides proof of concept that targeting Mst1r can modulate pancreatic cancer growth and the microenvironment. This study provides further rationale for targeting Mst1r as a therapeutic strategy. |
| Databáze: | OpenAIRE |
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