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

Jie Fang, Shivendra Singh, Changde Cheng, Sivaraman Natarajan, Heather Sheppard, Ahmed Abu-Zaid, Adam D. Durbin, Ha Won Lee, Qiong Wu, Jacob Steele, Jon P. Connelly, Hongjian Jin, Wenan Chen, Yiping Fan, Shondra M. Pruett-Miller, Jerold E. Rehg, Selene C. Koo, Teresa Santiago, Joseph Emmons, Stefano Cairo, Ruoning Wang, Evan S. Glazer, Andrew J. Murphy, Taosheng Chen, Andrew M. Davidoff, Carolina Armengol, John Easton, Xiang Chen () and Jun Yang ()
Additional contact information
Jie Fang: St. Jude Children’s Research Hospital
Shivendra Singh: St. Jude Children’s Research Hospital
Changde Cheng: St. Jude Children’s Research Hospital
Sivaraman Natarajan: St. Jude Children’s Research Hospital
Heather Sheppard: St. Jude Children’s Research Hospital
Ahmed Abu-Zaid: St. Jude Children’s Research Hospital
Adam D. Durbin: St. Jude Children’s Research Hospital
Ha Won Lee: St. Jude Children’s Research Hospital
Qiong Wu: St. Jude Children’s Research Hospital
Jacob Steele: St. Jude Children’s Research Hospital
Jon P. Connelly: St. Jude Children’s Research Hospital
Hongjian Jin: St. Jude Children’s Research Hospital
Wenan Chen: St. Jude Children’s Research Hospital
Yiping Fan: St. Jude Children’s Research Hospital
Shondra M. Pruett-Miller: St. Jude Children’s Research Hospital
Jerold E. Rehg: St. Jude Children’s Research Hospital
Selene C. Koo: St. Jude Children’s Research Hospital
Teresa Santiago: St. Jude Children’s Research Hospital
Joseph Emmons: St. Jude Children’s Research Hospital
Stefano Cairo: Champions Oncology, 1330 Piccard dr
Ruoning Wang: Abigail Wexner Research Institute, Nationwide Children’s Hospital
Evan S. Glazer: The University of Tennessee Health Science Center, 910 Madison Ave., Suite 325
Andrew J. Murphy: St. Jude Children’s Research Hospital
Taosheng Chen: St. Jude Children’s Research Hospital
Andrew M. Davidoff: St. Jude Children’s Research Hospital
Carolina Armengol: Childhood Liver Oncology Group, Germans Trias i Pujol Research Institute (IGTP), Translational Program in Cancer Research (CARE)
John Easton: St. Jude Children’s Research Hospital
Xiang Chen: St. Jude Children’s Research Hospital
Jun Yang: St. Jude Children’s Research Hospital

Nature Communications, 2023, vol. 14, issue 1, 1-27

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-39717-6

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