Pathway-based classification of glioblastoma uncovers a mitochondrial subtype with therapeutic vulnerabilities.
Pathway-based classification of glioblastoma uncovers a mitochondrial subtype with therapeutic vulnerabilities.
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DOI：
10.1038/s43018-020-00159-4
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发表时间：
2021-03
期刊：
影响因子：
22.7
通讯作者：
Iavarone A
中科院分区：
文献类型：
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作者：
Garofano L;Migliozzi S;Oh YT;D'Angelo F;Najac RD;Ko A;Frangaj B;Caruso FP;Yu K;Yuan J;Zhao W;Di Stefano AL;Bielle F;Jiang T;Sims P;Suvà ML;Tang F;Su XD;Ceccarelli M;Sanson M;Lasorella A;Iavarone A
胶质母细胞瘤（GBM）的转录组学分类未能预测生存率和治疗脆弱性。一种用于无偏鉴定单细胞和大块肿瘤的核心生物学特征的计算方法揭示了四种肿瘤细胞状态和GBM亚型，其沿着神经发育和代谢轴分布，分类为增殖/祖细胞、神经元、线粒体和糖酵解/多代谢。每个亚型都富含生物学上一致的多组学特征。线粒体GBM与最有利的临床结局相关。它完全依赖于氧化磷酸化的能量生产，而糖酵解/多代谢亚型是由有氧糖酵解和氨基酸和脂质代谢。葡萄糖质子同向转运体SLC 45 A1的缺失是与线粒体GBM最显著相关的主干改变，并且在线粒体胶质瘤细胞中重新引入SLC 45 A1诱导酸化和适应性丧失。线粒体，但不是糖酵解/多代谢，GBM表现出显着的脆弱性抑制剂的氧化磷酸化。GBM的基于通路的分类为生存提供信息，并使癌症代谢的精确靶向成为可能。
The transcriptomic classification of glioblastoma (GBM) has failed to predict survival and therapeutic vulnerabilities. A computational approach for unbiased identification of core biological traits of single cells and bulk tumors uncovered four tumor cell states and GBM subtypes distributed along neurodevelopmental and metabolic axes, classified as proliferative/progenitor, neuronal, mitochondrial and glycolytic/plurimetabolic. Each subtype was enriched with biologically coherent multiomic features. Mitochondrial GBM was associated with the most favorable clinical outcome. It relied exclusively on oxidative phosphorylation for energy production, whereas the glycolytic/plurimetabolic subtype was sustained by aerobic glycolysis and amino acid and lipid metabolism. Deletion of the glucose-proton symporter SLC45A1 was the truncal alteration most significantly associated with mitochondrial GBM, and the reintroduction of SLC45A1 in mitochondrial glioma cells induced acidification and loss of fitness. Mitochondrial, but not glycolytic/plurimetabolic, GBM exhibited marked vulnerability to inhibitors of oxidative phosphorylation. The pathway-based classification of GBM informs survival and enables precision targeting of cancer metabolism.
影响因子：
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作者：
Trifonov V;Pasqualucci L;Dalla Favera R;Rabadan R
通讯作者：
Rabadan R