LAUSR

Cholangiocarcinoma (CCA) is a poorly understood cancer of the biliary epithelium and the second most common type of liver cancer. Surgery currently offers the only potential for cure; however, most patients present with advanced disease and are therefore unresectable. The Cancer Genome Atlas (TCGA) analysis and other recent genomic studies have revealed discrete epigenetic perturbations amongst CCAs originating from different anatomic sites. Intrahepatic cholangiocarcinoma (ICC) arises from the intrahepatic bile ducts, and a subset of ICCs is characterized by loss-of-function mutations in the gene encoding for the chromatin regulatory factor BRCA associated protein 1 (BAP1). Loss of this protein may be associated with global epigenomic and transcriptomic alterations that ultimately contribute to tumor progression and metastasis dissemination. While elucidating the molecular pathogenesis of ICC may identify potential targeted therapies and improve early detection, inquiry into this disease has been hampered by a lack of genetically faithful animal models. We developed a genetically engineered mouse model (GEMM) of ICC that incorporates an inactivating mutation in BAP1 combined with Kras activation. An Albumin-Cre promoter was used to induce hepatoblast-specific mutations. Mutant Kras cooperates with loss of BAP1 and results in lethal hepatic transformation and dose-dependent survival. Kras activation alone results in extended disease latency and survival > 50 weeks. Loss of BAP1 alone or heterozygous loss of BAP1 combined with mutant Kras shortens disease latency, with mice surviving 39 weeks on average. A significant reduction in survival is seen with homozygous loss of BAP1 and Kras activation (Kras BAP1L/L). These mice survive on average 23 weeks (p ≤ 0.0045). Histopathologic evaluation of Kras BAP1L/L mice demonstrates focal biliary precursor lesions, frank ICC, and hepatocellular carcinoma (HCC). Mice with heterozygous deletion of BAP1 and Kras activation, loss of BAP1 alone, or Kras activation alone develop HCC only. Given the bipotential nature of hepatoblasts, the ICC phenotype of our GEMM may be enhanced by inducing biliary tree-specific mutations. Adenoviral Cre enzyme (Ad-Cre) is used to achieve such combinatorial specificity, and a novel surgery was developed whereby retrograde biliary tree administration of this enzyme is performed. Surgery utilizing GFP-tagged adeno-associated virus confirms administration targeted to the biliary tree. Retrograde biliary tree injection of Ad-Cre into ROSAmT/mG mice demonstrates Cre recombinase expression within cholangiocytes, thereby establishing proof-of-principle. Ad-Cre injection in Kras BAP1L/L mice to induce cholangiocyte-specific BAP1 deletion and Kras activation is ongoing. Citation Format: Rebecca Marcus, Wai Chin Foo, Anirban Maitra, Sonal Gupta. Development of a novel mouse model for intrahepatic cholangiocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1392. doi:10.1158/1538-7445.AM2017-1392