1. MST1R kinase accelerates pancreatic cancer progression via effects on both epithelial cells and macrophages
- Author
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Babicky, Michele L, Harper, Megan M, Chakedis, Jeffery, Cazes, Alex, Mose, Evangeline S, Jaquish, Dawn V, French, Randall P, Childers, Betzaira, Alakus, Hakan, Schmid, Michael C, Foubert, Phillippe, Miyamoto, Jaclyn, Holman, Patrick J, Walterscheid, Zakkary J, Tang, Chih-Min, Varki, Nissi, Sicklick, Jason K, Messer, Karen, Varner, Judith A, Waltz, Susan E, and Lowy, Andrew M
- Subjects
Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Immunology ,Pancreatic Cancer ,Rare Diseases ,Cancer ,Digestive Diseases ,Aetiology ,Development of treatments and therapeutic interventions ,5.1 Pharmaceuticals ,2.1 Biological and endogenous factors ,Animals ,Carcinoma ,Pancreatic Ductal ,Disease Progression ,Epithelial Cells ,Female ,Gene Knockdown Techniques ,Humans ,Intracellular Signaling Peptides and Proteins ,Macrophages ,Male ,Mice ,Mice ,Inbred C57BL ,Mice ,Transgenic ,Pancreatic Neoplasms ,Proof of Concept Study ,Protein Serine-Threonine Kinases ,Receptor Protein-Tyrosine Kinases ,Signal Transduction ,Tumor Microenvironment ,Clinical Sciences ,Oncology & Carcinogenesis ,Biochemistry and cell biology ,Oncology and carcinogenesis - Abstract
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.
- Published
- 2019