MST1R kinase accelerates pancreatic cancer progression via effects on both epithelial cells and macrophages

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...

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Published in:	Oncogene Vol. 38; no. 28; pp. 5599 - 5611
Main Authors:	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., Lowy, Andrew M.
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 01-07-2019 Nature Publishing Group
Subjects:	13/106 13/109 42/89 631/67/1504 631/67/327 64/60 82/1 82/51 Animal models Animals Apoptosis Arginase Carcinogenesis Carcinoma, Pancreatic Ductal - enzymology Carcinoma, Pancreatic Ductal - pathology Care and treatment Cell Biology Development and progression Disease Progression Epithelial cells Epithelial Cells - pathology Female Gene Knockdown Techniques Genetic aspects Genetic engineering Genetically modified mice Human Genetics Humans Internal Medicine Lymphocytes T Macrophages Macrophages - pathology Male Mannose Medicine Medicine & Public Health Metaplasia Metastases Mice Mice, Inbred C57BL Mice, Transgenic Oncology Pancreatic cancer Pancreatic Neoplasms - enzymology Pancreatic Neoplasms - pathology Proof of Concept Study Protein-Serine-Threonine Kinases - genetics Protein-Serine-Threonine Kinases - metabolism Receptor Protein-Tyrosine Kinases - genetics Receptor Protein-Tyrosine Kinases - metabolism Ron protein Signal Transduction Tumor Microenvironment Tumors
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Summary:	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.
Bibliography:	acquisition of data; (Babicky, Sood, Childers, Harper, Cazes, Mose, Jaquish, French, Alakus, Schmid, Foubert, Miyamoto, Holman, Walterscheid, Tang, Varki, Sicklick. obtained funding; (Lowy) statistical analysis; (Cazes, Jaquish, Messer, Lowy) study supervision; (Lowy) analysis and interpretation of data; (Babicky, Sood, Childers, Cazes, Lowy) drafting of the manuscript; (Babicky, Sood, Lowy) critical revision of the manuscript for important intellectual content; (Babicky, Jaquish, Varner, Waltz, Lowy) administrative, technical, or material support; (Cazes, Childers, Mose, Jaquish, French, Alakus, Schmid, Foubert, Miyamoto, Holman, Walterscheid, Tang, Varki, Sicklick, Waltz, Varner) Author contributions study concept and design; (Babicky, Waltz, Lowy)
ISSN:	0950-9232 1476-5594
DOI:	10.1038/s41388-019-0811-9