Abstract 140: Distinct pathways regulated by activated β-Catenin and YAP in hepatoblastoma pathogenesis

Abstract

Abstract Hepatoblastoma (HB) is a rare, yet the most common primary malignant hepatic liver in children. A significantly portion of children with HB have tumors that are not resected at diagnosis, leading to the dismal prognosis in these patients. Concomitant YAP and β-catenin activation could be seen 80% of HB. The signaling pathways regulated by YAP and β-catenin in HB pathogenesis remain unclear. Here, we engineered a inducible HB murine model using hydrodynamic injection to deliver transposon plasmids encoding constitutive YAP and doxycycline (Dox) inducible ΔN90-β-Catenin (Yap/TRE-β-Catenin). When fed with Dox, HB formed rapidly in the mice. Upon Dox withdraw, HB regressed over the long term. We analyzed gene expression patterns in mouse HB lesions upon short term Dox withdrawal, i.e, tumors still existed yet ΔN90-β-Catenin was turned off. This approach assisted to identify genes regulated by the activated β-Catenin in HB tumors. We compared these genes with the previously identified YAP regulated genes and found the distinct gene expression programs regulated by YAP and β-Catenin in HB. Specifically, YAP off down-regulated Hippo pathway and up-regulated metabolism-related pathways, whereas β-Catenin off down-regulated protein export, DNA replication pathway and up-regulated immune-related pathways. Finally, we identified ONECUT1 as a gene down-regulated by activated β-Catenin in HB. ONECUT1 expression was down-regulated in human HBs, and co-expression of ONECUT1 strongly suppressed Yap/β-Catenin HB formation in mice. Mechanically, ONECUT1 could regulate proliferation-related downstream signaling. Altogether our studies demonstrated that suppression of activated CTNNB1 mutations could repress HB progression in vivo, and we identified distinct pathways regulated by activated β-catenin and YAP in HB. Suppression of ONECUT1 expression by β-catenin is a key genetic event leading to HB formation. Citation Format: Weiting Liao, Xin Chen. Distinct pathways regulated by activated β-Catenin and YAP in hepatoblastoma pathogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 140.