Abstract 4135: AKT1 mediates PTEN-loss induced intrahepatic cholangiocarcinoma development in mice

Introduction: Liver cancer is the third most common cause of cancer-related mortality worldwide. Mice with liver-specific Pten loss (PtenloxP/loxP; albumin [Alb]-Cre-/+; LiPten) develop predominantly intrahepatic cholangiocarcinoma (ICC) and some hepatocellular carcinoma (HCC) by 12 months of age. Pten loss results in activation of the serine/threonine kinase AKT. Of the three AKT isoforms identified to date, AKT1 isoform is implicated in regulation of cell growth, proliferation, and survival. The present study investigated the role of AKT1 in mediating PTEN-loss induced liver cancer development. Methods: To generate mice with liver-specific Pten and Akt1 deletion (PtenloxP/loxP; Akt1loxP/loxP; Alb-Cre-/+; LiPtenA1), LiPten mice were crossed with mice that have liver-specific Akt1 loss (Akt1loxP/loxP; Alb-Cre-/+; LiA1). Whole livers from 12-month-old WT, LiA1, LiPten, and LiPtenA1 mice were analyzed for tumor prevalence and morphology via hematoxylin and eosin staining, and for markers of HCC and ICC via qPCR and immunofluorescence. Results: All male LiA1 mice displayed WT-like phenotype. Like LiPten mice, all male LiPtenA1 mice develop steatosis followed by tumors by 12 months of age. Compared to LiPten mice, LiPtenA1 animals displayed predominantly HCC phenotype based on morphology, increased HCC markers (Hnf4a, Alb), and decreased ICC markers (Sox9, Spp1, Hes1, Ck19). Conclusions: AKT1 loss in LiPten mice did not prevent development of steatosis and liver tumorigenesis but resulted in predominantly HCC rather than ICC phenotype, suggesting the role of AKT1 in mediating ICC development. These results contribute to the understanding of the role of AKT isoforms in regulating liver tumorigenesis, and further investigation into signaling mechanisms underlying these observations is required. Citation Format: Ielyzaveta Slarve, Yining Ding, Yushan Wang, Qi Tang, Zifei Xu, Lina He, Bangyan Stiles. AKT1 mediates PTEN-loss induced intrahepatic cholangiocarcinoma development in mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4135.