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RON Over-expression Induces Acinar-Ductal Metaplasia and Accelerates Tumorigenesis in a Kras Mutant Mouse Model of Pancreatic Cancer


RON is increasingly over-expressed during pancreatic cancer progression. It remains unclear whether RON plays a causal role in tumor formation, or if this aberrant expression represents an epiphenomenon. We hypothesized that RON over-expression accelerates pancreatic tumorigenesis in the presence of mutant Kras. We developed a novel transgenic mouse strain in which RON is specifically over-expressed in the pancreas (PDX-1-RON). We then studied the effects of RON over-expression alone and in the presence of mutant Kras, the earliest detectable mutation in pancreatic cancer³⁻⁸ (PDX-1-RON/LSL -KrasG¹²D/PDX-1-Cre , RCK). RCK mice demonstrated accelerated ADM and PanIN progression compared to mutant Kras only controls LSL-KrasG¹²D/PDX-1-Cre , CK). RCK mice displayed visible ADM foci and high grade PanIN as early as 6 weeks, with invasive carcinoma and metastasis detectable as early as 3 months. RCK mice had decreased survival compared to CK mice. Compared to controls, RCK mice displayed earlier and increased incidence of nuclear Phospho-[beta]-catenin (Y654), apical MMP7, and activated Notch1. Epithelial pancreatic cancer cell lines derived from this model that over-expressed RON mRNA also showed increased expression of [beta]-catenin and MSP, the RON ligand, mRNA. This work suggests two novel roles for RON signaling as a promoter of ADM : 1) via [beta]-catenin phosphorylation leading to increased MMP7 expression and subsequent Notch1 activation and 2) through Notch1 activation by increased expression of Delta1. This further validates RON as a potential therapeutic target in pancreatic cancer, and provides a useful model for studying the role of RON signaling in pancreatic tumor biology

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