RON overexpression accelerates tumorigenesis and induces metastasis in a KRAS mutant mouse model of pancreatic cancer

Abstract

Introduction The RON receptor is increasingly over-expressed during pancreatic cancer progression and has been implicated as a mediator of KRAS oncogene addiction. It remains unclear if RON promotes disease progression or simply represents an epiphenomenon. Methods To address this, we generated a transgenic mouse which over-expressed wt-RON in a pancreas-specific manner using Pdx-1, the identical promoter used to drive cre expression in the Kras-LSLGD12/Pdx-1-cre (KC) strain that develops pancreatic duct neoplasia. RON over-expression was verified via Western and IHC. Pdx-1/RON mice were crossed with LSL-KRASG12D mice to yield mice (RK), then bred to Pdx-1-Cre mice to combine RON over-expression in the presence of oncogenic KRAS (RCK). RCK mice were aged and sacrificed at various time points and histology compared to KC controls. Results Pdx-1-RON mice developed no pancreatic phenotype prior to 12 months. At 18 months, one of 4 animals developed primary pancreatic adenocarcinoma with lung metastasis. RON overexpression in KRAS mutant mice (RCK) led to accelerated PanIN progression compared to KC (p 1yr). Metastatic disease was visible in RCK mice at 9 months. Conclusions RON overexpression alone results in pancreatic cancer at long latency. In the presence of KRAS mutation, RON overexpression markedly accelerates PanIN progression to primary and metastatic pancreatic duct cancer. This data supports a role for RON in pancreatic carcinogenesis and this model may prove useful for investigations regarding the role of the RON receptor in pancreatic cancer biology.