Abstract
Lack of relevant animal models and cell lines of hepatoblastoma hampers our understanding pathogenesis of and identifying therapeutic targets for this neoplasm. We report a liver-specific MYC-driven hepatoblastoma murine model that faithfully recapitulates the pathological features of mixed fetal and embryonal hepatoblastoma, with transcriptomics resembling the high-risk gene signatures of human disease. Single-cell RNA-sequencing (scRNA-seq) and spatiotranscriptomics identified distinct subpopulations of hepatoblastoma cells. After deriving cell lines from the mouse model, we mapped the cancer dependency genes using CRISPR-Cas9 screening and identified druggable targets shared with human hepatoblastoma (i.e., CDK7, CDK9, PRMT1, PRMT5). Our screen also revealed oncogenes and tumor suppressor genes in hepatoblastoma that engage multiple, druggable cancer signaling pathways. Chemotherapy is the mainstay for human hepatoblastoma treatment. A genetic mapping of doxorubicin response by CRISPR-Cas9 screening identified modifiers whose loss-of-function synergizes and antagonizes with the effect of chemotherapy. The combination of PRKDC inhibition and chemotherapy greatly enhances therapeutic efficacy. Our studies have provided and characterized useful resources including disease models and identified potential therapeutic targets of high-risk hepatoblastoma.
Citation Format: Jun Yang. Genome-wide mapping of oncogenic pathways and genetic modifiers of chemotherapy using a high-risk hepatoblastoma genetic model [abstract]. In: Proceedings of the AACR Special Conference: Advances in the Pathogenesis and Molecular Therapies of Liver Cancer; 2022 May 5-8; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(17_Suppl):Abstract nr PO014.
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