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 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 MST1R/RON receptor tyrosine kinase is a homologue of the more well-known MET receptor. Like MET, RON orchestrates cell signaling pathways that promote oncogenesis and enable cancer cell survival; however, it has a more unique role in the regulation of inflammation. RON was originally described as a transmembrane receptor expressed on tissue resident macrophages and various epithelial cells. RON is overexpressed in a variety of cancers and its activation modifies multiple signaling pathways with resultant changes in epithelial and immune cells which together modulate oncogenic phenotypes. While several RON isoforms have been identified with differences in structure, activation, and pathway regulation, increased RON expression and/or activation is consistently associated with worse outcomes. Tyrosine kinase inhibitors targeting RON have been developed, making RON an actionable therapeutic target.

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2001 to 2016 were retrospectively collected. Clinicopathologic factors were correlated with the primary outcome of overall survival in univariate and multivariate analyses. Results: 330 patients were surgically treated between 2001 and 2016. The majority of patients presented with early stage disease (Stage I-15.9%, Stage II-81.4%, Stage III-1.7%). Twenty-one patients (10.3%) received neoadjuvant therapy and 221 (72.5%) completed adjuvant therapy. Median survival was 26.8 months, with 1-,3-,and 5-year overall survival of 77.1%, 41.2%, and 28.4%. Median follow-up time was 21.7 months. Pathologic findings of lymphovascular invasion (p < 0.0001), perineural invasion (p = 0.0089), and lymph node invasion (p < 0.0001) were significantly associated with worse survival on univariate analysis. Tumor size >1.5 cm (p = 0.0063), lymph node ratio >0.1 (p = 0.0003), and a non-R0 resection (p = 0.0002) were also significantly associated with worse survival. Tumor stage, major surgical complications (Clavien-Dindo 3), and local tumor recurrence were independently associated with worse survival on multivariate analysis (p < 0.05). There were no significant associations between survival and operation type, preoperative presenting symptoms, or neoadjuvant or adjuvant therapy. Conclusion: This is the largest series analyzing PDAC-NBT who underwent surgical therapy. Improved survival is associated with favorable tumor biology and operative outcomes.