Genome-wide mapping of cancer dependency genes and genetic modifiers of chemotherapy in high-risk hepatoblastoma.
Genome-wide mapping of cancer dependency genes and genetic modifiers of chemotherapy in high-risk hepatoblastoma.
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DOI：
10.1038/s41467-023-39717-6
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发表时间：
2023-07-06
影响因子：
16.6
通讯作者：
Yang, Jun
中科院分区：
文献类型：
--
作者：
Fang, Jie;Singh, Shivendra;Cheng, Changde;Natarajan, Sivaraman;Sheppard, Heather;Abu-Zaid, Ahmed;Durbin, Adam D.;Lee, Ha Won;Wu, Qiong;Steele, Jacob;Connelly, Jon P.;Jin, Hongjian;Chen, Wenan;Fan, Yiping;Pruett-Miller, Shondra M.;Rehg, Jerold E.;Koo, Selene C.;Santiago, Teresa;Emmons, Joseph;Cairo, Stefano;Wang, Ruoning;Glazer, Evan S.;Murphy, Andrew J.;Chen, Taosheng;Davidoff, Andrew M.;Armengol, Carolina;Easton, John;Chen, Xiang;Yang, Jun
缺乏相关的遗传模型和细胞系阻碍了我们对肝母细胞瘤发病机制的理解和这种肿瘤新疗法的开发。在这里，我们报告了一种改进的MYC驱动的肝母细胞瘤样小鼠模型，该模型概括了胚胎型肝母细胞瘤的病理特征，其转录组学类似于人类疾病的高风险基因特征。单细胞RNA测序和空间转录组学鉴定肝母细胞瘤细胞的不同亚群从小鼠模型中获得细胞系后，我们使用CRISPR-Cas9筛选绘制癌症依赖性基因，并鉴定与人类肝母细胞瘤共有的可药物靶点（例如，CDK7、CDK9、PRMT1、PRMT5）。我们的筛选还揭示了肝母细胞瘤中的癌基因和肿瘤抑制基因，它们参与了多种可药物化的癌症信号通路。化疗是人类肝母细胞瘤治疗的关键。通过CRISPR-Cas9筛选对多柔比星反应进行基因图谱分析，识别出功能丧失与（例如，PRKDC）或拮抗（例如，凋亡基因）化疗的影响。PRKDC抑制和基于阿霉素的化疗的组合极大地增强了治疗功效。这些研究提供了一系列资源，包括适合于识别和验证人类高危肝母细胞瘤潜在治疗靶点的疾病模型。相关的动物模型，可以概括高危肝母细胞瘤的可用性将有助于更好地了解其发病机制。在这里，作者报告并描述了一种肝细胞特异性的MYC驱动的肝母细胞瘤小鼠模型，并表明它概括了人类肝母细胞瘤的病理生理学。
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.
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影响因子：
12.3
作者：
Chen W;Li Y;Easton J;Finkelstein D;Wu G;Chen X
通讯作者：
Chen X
影响因子：
8
作者：
Comerford, Sarah A.;Hinnant, Elizabeth A.;Hammer, Robert E.
通讯作者：
Hammer, Robert E.
影响因子：
30.8
作者：
Dharia NV;Kugener G;Guenther LM;Malone CF;Durbin AD;Hong AL;Howard TP;Bandopadhayay P;Wechsler CS;Fung I;Warren AC;Dempster JM;Krill-Burger JM;Paolella BR;Moh P;Jha N;Tang A;Montgomery P;Boehm JS;Hahn WC;Roberts CWM;McFarland JM;Tsherniak A;Golub TR;Vazquez F;Stegmaier K
通讯作者：
Stegmaier K
影响因子：
8.4
作者：
Cairo, Stefano;Armengol, Carolina;Kappler, Roland
通讯作者：
Kappler, Roland
影响因子：
5.2
作者：
Street CA;Routhier AA;Spencer C;Perkins AL;Masterjohn K;Hackathorn A;Montalvo J;Dennstedt EA;Bryan BA
通讯作者：
Bryan BA