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

Oncogene volume 38, pages 5599–5611 (2019)Cite this article

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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.

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Funding

This work was supported by NIH CA155620 (AML), NIH T32CA121938 (MLB), Ride the Point (AML) and generous gifts to the Sally Ride Fund for Pancreatic Cancer Research (AML) and the Cure Pancreatic Cancer Fund (AML).

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Authors and Affiliations

  1. Division of Surgical Oncology, Department of Surgery, University of California, San Diego, La Jolla, CA, 92093, USA

    Michele L. Babicky, Megan M. Harper, Jeffery Chakedis, Alex Cazes, Evangeline S. Mose, Dawn V. Jaquish, Randall P. French, Betzaira Childers, Hakan Alakus, Jaclyn Miyamoto, Patrick J. Holman, Zakkary J. Walterscheid, Chih-Min Tang, Jason K. Sicklick & Andrew M. Lowy

  2. Department of Pathology, University of California, San Diego, La Jolla, CA, 92093, USA

    Michael C. Schmid, Phillippe Foubert & Judith A. Varner

  3. Department of Family Medicine and Epidemiology, University of California, San Diego, La Jolla, CA, 92093, USA

    Nissi Varki & Karen Messer

  4. Department of Cancer Biology, University of Cincinnati College of Medicine, and Research Service, Cincinnati Veteran’s Administration Medical Center, Cincinnati, OH, 45267, USA

    Susan E. Waltz

Authors
  1. Michele L. Babicky
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  2. Megan M. Harper
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Contributions

Study concept and design: MLB, SEW, and AML. Acquisition of data: MLB, BC, MMH, AC, ESM, DVJ, RPF, HA, MCS, PF, JM, PJH, ZJW, C-MT, NV, and JKS). Analysis and interpretation of data: MLB, BC, AC, and AML. Drafting of the manuscript: MLB, and AML. Critical revision of the manuscript for important intellectual content: MLB, DVJ, JAV, SEW, and AML. Statistical analysis: AC, DVJ, KM, and AML. Obtained funding: AML. Administrative, technical, or material support: AC, BC, ESM, DVJ, RPF, HA, MCS, PF, JM, PJH, ZJW, C-MT, NV, JKS, SEW, and JAV. Study supervision: AML.

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Correspondence to Andrew M. Lowy.

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Babicky, M.L., Harper, M.M., Chakedis, J. et al. MST1R kinase accelerates pancreatic cancer progression via effects on both epithelial cells and macrophages. Oncogene 38, 5599–5611 (2019). https://doi.org/10.1038/s41388-019-0811-9

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