論文掲載：St. Jude Children's Research Hospital、高リスク肝芽腫におけるがん依存性遺伝子と化学療法に寄与する遺伝的修飾因子のゲノムワイドマッピング

Nature Communications
July 10, 2023

本論文では、ヒト疾患の高リスク遺伝子シグネチャーに類似したトランスクリプトミクスを持つ、改良されたMYC駆動型肝芽腫様マウスモデルを報告しています。本研究において、ハイスループット細胞毒性アッセイの解析にGenedata Screenerが使用されました。

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.

Genedata Screener was used to analyze a cytoxicity assay, in a high-throughput screen for therapies against MYC-driven hepatoblastoma.