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


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 ORCID: 0000-0002-3445-0013 et al (show 11 more authors) (2019) MST1R kinase accelerates pancreatic cancer progression via effects on both epithelial cells and macrophages. ONCOGENE, 38 (28). pp. 5599-5611.

[img] Text
Oncogene 2019.pdf - Author Accepted Manuscript
Download (12MB)

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.

Item Type: Article
Uncontrolled Keywords: Macrophages, Epithelial Cells, Animals, Mice, Inbred C57BL, Mice, Transgenic, Humans, Mice, Carcinoma, Pancreatic Ductal, Pancreatic Neoplasms, Disease Progression, Receptor Protein-Tyrosine Kinases, Intracellular Signaling Peptides and Proteins, Signal Transduction, Female, Male, Gene Knockdown Techniques, Tumor Microenvironment, Proof of Concept Study, Protein Serine-Threonine Kinases
Depositing User: Symplectic Admin
Date Deposited: 22 Mar 2019 15:26
Last Modified: 19 Jan 2023 00:56
DOI: 10.1038/s41388-019-0811-9
Related URLs:
URI: https://livrepository.liverpool.ac.uk/id/eprint/3034675
Dimensions
Altmetric
CORE (COnnecting REpositories)