在胶质母细胞瘤中,细胞对 GPX4 依赖性铁氧化作用的代谢脆弱性具有特异性。

IF 9.4 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
EMBO Journal Pub Date : 2024-10-01 Epub Date: 2024-08-27 DOI:10.1038/s44318-024-00176-4
Matei A Banu, Athanassios Dovas, Michael G Argenziano, Wenting Zhao, Colin P Sperring, Henar Cuervo Grajal, Zhouzerui Liu, Dominique Mo Higgins, Misha Amini, Brianna Pereira, Ling F Ye, Aayushi Mahajan, Nelson Humala, Julia L Furnari, Pavan S Upadhyayula, Fereshteh Zandkarimi, Trang Tt Nguyen, Damian Teasley, Peter B Wu, Li Hai, Charles Karan, Tyrone Dowdy, Aida Razavilar, Markus D Siegelin, Jan Kitajewski, Mioara Larion, Jeffrey N Bruce, Brent R Stockwell, Peter A Sims, Peter Canoll
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引用次数: 0

摘要

胶质瘤细胞劫持发育程序来控制细胞状态。在这里,我们发现了胶质瘤细胞特定状态下的代谢责任,这种责任可以作为治疗目标。为了模拟脑肿瘤发生时的细胞状态,我们生成了基因工程小鼠胶质瘤,这些胶质瘤单独缺失了 p53(p53),或具有构成性活跃的 Notch 信号(N1IC),Notch 信号是大脑发育过程中控制星形胶质细胞分化的关键通路。N1IC肿瘤含有静止的星形胶质细胞样转化细胞群,而p53肿瘤则主要由增殖的祖细胞样细胞组成。此外,N1IC 转化细胞表现出线粒体脂质过氧化增加、高 ROS 生成和还原型谷胱甘肽耗竭。这种线粒体表型的改变使类似星形胶质细胞的静止细胞群对药物或基因抑制脂质过氧化物酶 GPX4 和诱导铁变态反应更加敏感。用 GPX4 抑制剂处理患者衍生的早期细胞系和手术样本产生的胶质瘤切片培养物,可选择性地消耗具有类似代谢特征的静止星形胶质细胞样胶质瘤细胞群。总之,这些发现揭示了在对标准治疗方式有抵抗力的静止星形胶质细胞样胶质瘤细胞亚群中,铁氧化还原失衡与线粒体氧化还原失衡有关的特定治疗脆弱性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
A cell state-specific metabolic vulnerability to GPX4-dependent ferroptosis in glioblastoma.

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.

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来源期刊
EMBO Journal
EMBO Journal 生物-生化与分子生物学
CiteScore
18.90
自引率
0.90%
发文量
246
审稿时长
1.5 months
期刊介绍: The EMBO Journal has stood as EMBO's flagship publication since its inception in 1982. Renowned for its international reputation in quality and originality, the journal spans all facets of molecular biology. It serves as a platform for papers elucidating original research of broad general interest in molecular and cell biology, with a distinct focus on molecular mechanisms and physiological relevance. With a commitment to promoting articles reporting novel findings of broad biological significance, The EMBO Journal stands as a key contributor to advancing the field of molecular biology.
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