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 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

The Role of Interleukin-11 in Pancreatic Cancer Progression /

Pancreatic cancer patients have a five-year survival rate of approximately 6%, far worse than any other common malignancy. Clearly a greater understanding of the multiple signaling pathways involved in pancreatic cancer progression is needed to develop more effective treatment for this devastating disease. Interleukin-11 (IL-11) is a member of the IL-6 class of cytokines and has been implicated in the development and/or progression of multiple human cancers. IL-11 promotes inflammation involved in tumor progression, cell migration and proliferation, differentiation of tumor cells in the tumor microenvironment, invasiveness, and survival. However, the role of IL-11 in pancreatic cancer is largely unknown. In this study, we show that the IL-11 ligand is overexpressed in pancreatic cancer. In cultured pancreatic cancer cells, IL-11 signaling activates the Akt, ERK, and Stat3 signaling pathways, yet IL-11 has no effect on cell proliferation or migration. We demonstrate that TGF-[Beta] increases IL-11 expression by pancreatic cancer associated fibroblasts (CAFs), an effect mediated by the ERK signaling pathway. Our results thus far show IL-11 activates core oncogenic signaling pathways in pancreatic cancer cells and thus IL-11 signaling may help promote pancreatic cancer progression. Further studies are necessary to better define the oncogenic phenotypes impacted by IL-11 in the pancreatic cancer microenvironmen

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 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