Genome-Wide CRISPR-Cas9 Screens Expose Genetic Vulnerabilities and Mechanisms of Temozolomide Sensitivity in Glioblastoma Stem Cells
Genome-Wide CRISPR-Cas9 Screens Expose Genetic Vulnerabilities and Mechanisms of Temozolomide Sensitivity in Glioblastoma Stem Cells
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DOI：
10.1016/j.celrep.2019.03.047
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发表时间：
2019-04-16
期刊：
影响因子：
8.8
通讯作者：
Angers, Stephane
中科院分区：
文献类型：
--
作者：
MacLeod, Graham;Bozek, Danielle A.;Angers, Stephane
胶质母细胞瘤的治疗仍然是难以捉摸的，由于了解机制的限制生长和生存的致瘤性人群。利用CRISPR-Cas9方法在患者来源的GBM干细胞（GSCs）中询问编码基因组的功能，我们确定了负责生长的可操作途径，揭示了GBM干细胞和增殖的基因必需电路。特别地，我们描述了SOX转录因子家族的成员，SOCS3， USP8和DOT1L，以及蛋白质甲基化对GSC生长很重要。此外，我们揭示了替莫唑胺耐药的机制，可能导致联合策略。通过对大块肿瘤的静态基因组分析，采用全基因组功能方法，我们揭示了广泛生物过程中的遗传依赖性，从而增加了对GBM生长和治疗耐药性的了解。
Glioblastoma therapies have remained elusive due to limitations in understanding mechanisms of growth and survival of the tumorigenic population. Using CRISPR-Cas9 approaches in patient-derived GBM stem cells (GSCs) to interrogate function of the coding genome, we identify actionable pathways responsible for growth, which reveal the gene-essential circuitry ofGBMstemness and proliferation. In particular, we characterize members of the SOX transcription factor family, SOCS3, USP8, and DOT1L, and protein ufmylation as important for GSC growth. Additionally, we reveal mechanisms of temozolomide resistance that could lead to combination strategies. By reaching beyond static genome analysis of bulk tumors, with a genome-wide functional approach, we reveal genetic dependencies within a broad range of biological processes to provide increased understanding of GBM growth and treatment resistance.