Cholangiocarcinoma tumorigenesis in Abcb4(Mdr2)-/- and wild-type mice by transposon-based oncogenes integration

Cholangiocarcinoma (CCA) is a dreaded complication of primary sclerosing cholangitis (PSC), difficult to diagnose and associated with high mortality. Lack of animal models of CCA recapitulating the hepatic microenvironment of sclerosing cholangitis hinders development of novel treatments. We have developed and characterized a new mouse model of PSC-CCA through hydrodynamic tail vein injection of oncogenes pT3-EF1a-HA-myrAKT (AKT) and pT3-EF1a-YapS127A (YAP1), termed SB CCA.Mdr2-/-, which features reliable tumor induction in PSC-like background of biliary injury and fibrosis. To unravel the potential molecular profile of CCA developed in different liver context, we profiled the transcriptomes of tumor-bearing fibrotic (Mdr2-/-) (n = 6) and tumor-bearing wild-type liver tissues (n = 6) and compared to corresponding control nontumor-bearing fibrotic (Mdr2-/-) (n = 6) and healthy liver tissues (n = 6). RNA-seq analysis revealed profound transcriptional differences in CCA evolving in PSC-like context, compared to CCA in healthy liver. Overall design: Profiling of individual tumor-bearing liver tissues with transduction of AKT/YAP1 (CCA.Mdr2-/- and CCA.Wild-type, n = 6 for each) and context matched non-tumor liver tissues with empty transduction (Ctrl.Mdr2-/- and Ctrl.Wild-type. Differentially expressed genes were determined from 2 comparisons: CCA.Mdr2-/- vs. Ctrl.Mdr2-/-, and CCA.Wild-type and Ctrl.WT.