A cell state specific metabolic vulnerability to GPX4-dependent ferroptosis in glioblastoma.
A cell state specific metabolic vulnerability to GPX4-dependent ferroptosis in glioblastoma.
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胶质母细胞瘤中 GPX4 依赖性铁死亡的细胞状态特异性代谢脆弱性。
DOI：
10.1101/2023.02.22.529581
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Zandkarimi,F
中科院分区：
文献类型：
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作者：
Banu,MateiA;Dovas,Athanassios;Argenziano,MichaelG;Zhao,Wenting;Grajal,HenarCuervo;Higgins,DominiqueMO;Sperring,ColinP;Pereira,Brianna;Ye,LingF;Mahajan,Aayushi;Humala,Nelson;Furnari,JuliaL;Upadhyayula,PavanS;Zandkarimi,F
胶质瘤细胞通过劫持发育程序来控制细胞状态。在这里，我们发现胶质瘤细胞状态特异性代谢倾向，可以治疗靶向。为了模拟脑肿瘤发生时的细胞状况，我们产生了基因工程小鼠胶质瘤，缺失p53 （p53）或构成活性Notch信号（N1IC），这是在大脑发育过程中控制星形胶质细胞分化的关键途径。N1IC肿瘤含有静止的星形细胞样转化细胞群，而p53肿瘤主要由增殖的祖细胞样细胞状态组成。此外，N1IC转化的细胞表现出线粒体脂质过氧化增加，ROS产生高，还原性谷胱甘肽耗竭。这种线粒体表型的改变使星形细胞样的静止种群对脂质氢过氧化物酶GPX4的药理学或遗传抑制和铁下垂的诱导更敏感。用GPX4抑制剂治疗患者来源的早期传代细胞系和手术样本生成的胶质瘤切片培养物，诱导具有相似代谢谱的静止星形细胞样胶质瘤细胞群选择性耗散。总的来说，这些发现揭示了静止星形细胞样胶质瘤细胞亚群中对标准治疗形式有抵抗力的线粒体氧化还原失衡与铁凋亡的特定治疗脆弱性。
Glioma cells hijack developmental programs to control cell state. Here, we uncover a glioma cell state-specific metabolic liability that can be therapeutically targeted. To model cell conditions at brain tumor inception, we generated genetically engineered murine gliomas, with deletion of p53 alone (p53) or with constitutively active Notch signaling (N1IC), a pathway critical in controlling astrocyte differentiation during brain development. N1IC tumors harbored quiescent astrocyte-like transformed cell populations while p53 tumors were predominantly comprised of proliferating progenitor-like cell states. Further, N1IC transformed cells exhibited increased mitochondrial lipid peroxidation, high ROS production and depletion of reduced glutathione. This altered mitochondrial phenotype rendered the astrocyte-like, quiescent populations more sensitive to pharmacologic or genetic inhibition of the lipid hydroperoxidase GPX4 and induction of ferroptosis. Treatment of patient-derived early-passage cell lines and glioma slice cultures generated from surgical samples with a GPX4 inhibitor induced selective depletion of quiescent astrocyte-like glioma cell populations with similar metabolic profiles. Collectively, these findings reveal a specific therapeutic vulnerability to ferroptosis linked to mitochondrial redox imbalance in a subpopulation of quiescent astrocyte-like glioma cells resistant to standard forms of treatment.