Genome-wide mapping of oncogenic pathways and genetic modifiers of chemotherapy using a high-risk hepatoblastoma genetic model

ABSTRACT: Lack of relevant disease animal models and cell lines hampers our understanding of hepatoblastoma and identification of therapeutic targets. We report a liver-specific MYC-driven hepatoblastoma murine model that faithfully recapitulates the pathological features of mixed fetal and embryonic hepatoblastoma, with transcriptomics resembling the high-risk gene signatures of human disease. Single-cell RNA-sequencing (scRNA-seq) and spatiotranscriptomics identify a subpopulation of hepatoblastoma cells with high levels of adult hemoglobin genes. After deriving a cell line from the mouse model, we mapped the cancer dependency genes using CRISPR-Cas9 and identified druggable targets shared with human hepatoblastoma (i.e., CDK7, CDK9, PRMT1, PRMT5). Our screen also discovered oncogenes and tumor suppressive genes in hepatoblastoma that engage multiple cancer signaling pathways. Chemotherapy is the mainstay of human hepatoblastoma. Genetic map of doxorubicin response by CRISPR-Cas9 identified modifiers whose loss-of-function synergizes (PRKDC) and antagonizes (Polycomb repressive complex 2) the effect of chemotherapy. Combination of PRKDC inhibitor and chemotherapy greatly enhances therapeutic efficacy. Our studies have provided useful disease models and potential therapeutic targets of hepatoblastoma.

ORGANISM(S): Mus musculus

PROVIDER: GSE193124 | GEO | 2023/06/22

REPOSITORIES: GEO