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Abstract 4083: Intrahepatic cholangiocarcinoma and gallbladder carcinoma mouse model based on transplantation of syngeneic tumor-initiating cells

Biliary tract cancers (BTCs) are relatively rare in the Western world, but the rates of BTCs have risen worldwide in the past few decades. BTCs, which arise from epithelial cells in bile ducts, include intrahepatic and extrahepatic cholangiocarcinomas, gallbladder carcinomas, and ampullary carcinomas. The differences between these subtypes are not fully understood because of the limited number of genetically engineered mouse models for BTCs. Genetic mutations in the KRAS gene and the epigenetic changes in Ink4a/Arf genes have been frequently detected in BTCs, and it has been considered that those alterations are associated with the development and maintenance of human BTCs. To clarify the biological features of intrahepatic cholangiocarcinomas and gallbladder carcinomas, we developed syngeneic mouse models based on a combination of organoid 3D cultures and the transplantation of oncogene-expressed syngeneic bile duct epithelial cells. We isolated the epithelial cell adhesion molecule (EpCAM)-positive intrahepatic bile duct epithelial cells and the gallbladder epithelial cells from the Ink4a/Arf knockout C57BL/6 mice, and the cells were maintained as organoids under 3D culture conditions. Those cells were then infected with retroviruses expressing KRASG12V. Lethal metastatic adenocarcinomas having differentiated components formed in our mice when we transplanted the KRASG12V-expressing cells into the livers of wild-type C57BL/6 mice. The tumors resembled human desmoplastic intrahepatic cholangiocarcinomas and gallbladder carcinomas. Our mouse models can be useful for investigating pathogenesis and therapeutic strategies for human BTCs. Citation Format: Akiyoshi Kasuga, Takashi Semba, Hiromasa Takaishi, Takanori Kanai, Hideyuki Saya, Yoshimi Arima. Intrahepatic cholangiocarcinoma and gallbladder carcinoma mouse model based on transplantation of syngeneic tumor-initiating cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4083.