Genome-wide mapping of cancer dependency genes and genetic modifiers of chemotherapy in high-risk hepatoblastoma
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...
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| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2023-07-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-39717-6 |
| _version_ | 1797784553537929216 |
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| author | 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 Jun Yang |
| author_facet | 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 Jun Yang |
| author_sort | Jie Fang |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-13T00:41:32Z |
| format | Article |
| id | doaj.art-518df2bf603d4dbaa5922a65b63e4a51 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-13T00:41:32Z |
| publishDate | 2023-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-518df2bf603d4dbaa5922a65b63e4a512023-07-09T11:17:43ZengNature PortfolioNature Communications2041-17232023-07-0114112710.1038/s41467-023-39717-6Genome-wide mapping of cancer dependency genes and genetic modifiers of chemotherapy in high-risk hepatoblastomaJie Fang0Shivendra Singh1Changde Cheng2Sivaraman Natarajan3Heather Sheppard4Ahmed Abu-Zaid5Adam D. Durbin6Ha Won Lee7Qiong Wu8Jacob Steele9Jon P. Connelly10Hongjian Jin11Wenan Chen12Yiping Fan13Shondra M. Pruett-Miller14Jerold E. Rehg15Selene C. Koo16Teresa Santiago17Joseph Emmons18Stefano Cairo19Ruoning Wang20Evan S. Glazer21Andrew J. Murphy22Taosheng Chen23Andrew M. Davidoff24Carolina Armengol25John Easton26Xiang Chen27Jun Yang28Department of Surgery, St. Jude Children’s Research HospitalDepartment of Surgery, St. Jude Children’s Research HospitalDepartment of Computational Biology, St. Jude Children’s Research HospitalDepartment of Computational Biology, St. Jude Children’s Research HospitalComparative Pathology Core, St. Jude Children’s Research HospitalDepartment of Surgery, St. Jude Children’s Research HospitalDivision of Molecular Oncology, Department of Oncology, St. Jude Children’s Research HospitalDepartment of Chemical Biology and Therapeutics, St. Jude Children’s Research HospitalDepartment of Surgery, St. Jude Children’s Research HospitalCenter for Advanced Genome Engineering (CAGE), St. Jude Children’s Research HospitalCenter for Advanced Genome Engineering (CAGE), St. Jude Children’s Research HospitalCenter for Applied Bioinformatics, St. Jude Children’s Research HospitalCenter for Applied Bioinformatics, St. Jude Children’s Research HospitalCenter for Applied Bioinformatics, St. Jude Children’s Research HospitalCenter for Advanced Genome Engineering (CAGE), St. Jude Children’s Research HospitalComparative Pathology Core, St. Jude Children’s Research HospitalDepartment of Pathology, St. Jude Children’s Research HospitalDepartment of Pathology, St. Jude Children’s Research HospitalVPC Diagnostic Laboratory, St. Jude Children’s Research HospitalChampions Oncology, 1330 Piccard drCenter for Childhood Cancer and Blood Disease, Hematology/Oncology & BMT, Abigail Wexner Research Institute, Nationwide Children’s HospitalDepartment of Surgery, College of Medicine, The University of Tennessee Health Science Center, 910 Madison Ave., Suite 325Department of Surgery, St. Jude Children’s Research HospitalDepartment of Chemical Biology and Therapeutics, St. Jude Children’s Research HospitalDepartment of Surgery, St. Jude Children’s Research HospitalChildhood Liver Oncology Group, Germans Trias i Pujol Research Institute (IGTP), Translational Program in Cancer Research (CARE)Department of Computational Biology, St. Jude Children’s Research HospitalDepartment of Computational Biology, St. Jude Children’s Research HospitalDepartment of Surgery, St. Jude Children’s Research HospitalAbstract 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.https://doi.org/10.1038/s41467-023-39717-6 |
| spellingShingle | 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 Jun Yang Genome-wide mapping of cancer dependency genes and genetic modifiers of chemotherapy in high-risk hepatoblastoma Nature Communications |
| title | Genome-wide mapping of cancer dependency genes and genetic modifiers of chemotherapy in high-risk hepatoblastoma |
| title_full | Genome-wide mapping of cancer dependency genes and genetic modifiers of chemotherapy in high-risk hepatoblastoma |
| title_fullStr | Genome-wide mapping of cancer dependency genes and genetic modifiers of chemotherapy in high-risk hepatoblastoma |
| title_full_unstemmed | Genome-wide mapping of cancer dependency genes and genetic modifiers of chemotherapy in high-risk hepatoblastoma |
| title_short | Genome-wide mapping of cancer dependency genes and genetic modifiers of chemotherapy in high-risk hepatoblastoma |
| title_sort | genome wide mapping of cancer dependency genes and genetic modifiers of chemotherapy in high risk hepatoblastoma |
| url | https://doi.org/10.1038/s41467-023-39717-6 |
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