Genome-wide mapping of cancer dependency genes and genetic modifiers of chemotherapy in high-risk hepatoblastoma

A lack of relevant genetic models and cell lines hampers our understanding of hepatoblastoma pathogenesis and the development of new therapies for this neoplasm. Here, we report an improved MYC-driven hepatoblastoma-like murine model that recapitulates the pathological features of embryonal type of hepatoblastoma, with transcriptomics resembling the high-risk gene signatures of the human disease. Single-cell RNA-sequencing and spatial transcriptomics identify distinct subpopulations of hepatoblastoma cells. After deriving cell lines from the mouse model, we map cancer dependency genes using CRISPR-Cas9 screening and identify druggable targets shared with human hepatoblastoma (e.g., CDK7, CDK9, PRMT1, PRMT5). Our screen also reveals oncogenes and tumor suppressor genes in hepatoblastoma that engage multiple, druggable cancer signaling pathways. Chemotherapy is critical for human hepatoblastoma treatment. A genetic mapping of doxorubicin response by CRISPR-Cas9 screening identifies modifiers whose loss-of-function synergizes with (e.g., PRKDC) or antagonizes (e.g., apoptosis genes) the effect of chemotherapy. The combination of PRKDC inhibition and doxorubicin-based chemotherapy greatly enhances therapeutic efficacy. These studies provide a set of resources including disease models suitable for identifying and validating potential therapeutic targets in human high-risk hepatoblastoma. The availability of relevant animal models that can recapitulate high-risk hepatoblastoma will help to better understand its pathogenesis. Here the authors report and characterize a hepatocyte-specific, MYC-driven hepatoblastoma mouse model and show it recapitulates the human hepatoblastoma pathophysiology.

Automated summary

A improved MYC-driven hepatoblastoma-like murine model is developed and characterized in this study, which recapitulates the pathological features of embryonal type of hepatoblastoma and shows transcriptomics resembling the high-risk gene signatures of the human disease. Single-cell RNA-sequencing and CRISPR-Cas9 screening are used to identify distinct subpopulations of hepatoblastoma cells and druggable targets shared with human hepatoblastoma. The study also reveals genetic modifiers of chemotherapy response and suggests a potential therapeutic strategy for human hepatoblastoma.