CNRS UMR8246, Inserm U1130, Sorbonne Université, Neuroscience Paris Seine-IBPS Laboratory, Team Glial Plasticity and NeuroOncology, Paris, France.
CNRS UMR5095, Inserm U1029, Université de Bordeaux, Institut de Biochimie et Génétique Cellulaires, Team Bioenergetics and dynamics of mitochondria, Bordeaux, France.
Cell Death Dis. 2022 Oct 30;13(10):913. doi: 10.1038/s41419-022-05358-8.
Cell motility is critical for tumor malignancy. Metabolism being an obligatory step in shaping cell behavior, we looked for metabolic weaknesses shared by motile cells across the diverse genetic contexts of patients' glioblastoma. Computational analyses of single-cell transcriptomes from thirty patients' tumors isolated cells with high motile potential and highlighted their metabolic specificities. These cells were characterized by enhanced mitochondrial load and oxidative stress coupled with mobilization of the cysteine metabolism enzyme 3-Mercaptopyruvate sulfurtransferase (MPST). Functional assays with patients' tumor-derived cells and -tissue organoids, and genetic and pharmacological manipulations confirmed that the cells depend on enhanced ROS production and MPST activity for their motility. MPST action involved protection of protein cysteine residues from damaging hyperoxidation. Its knockdown translated in reduced tumor burden, and a robust increase in mice survival. Starting from cell-by-cell analyses of the patients' tumors, our work unravels metabolic dependencies of cell malignancy maintained across heterogeneous genomic landscapes.
细胞迁移对于肿瘤恶性程度至关重要。代谢是塑造细胞行为的必要步骤，因此我们寻找了在患者脑胶质瘤不同遗传背景下迁移细胞共有的代谢弱点。对来自 30 名患者肿瘤的单细胞转录组进行计算分析，分离出具有高迁移潜能的细胞，并突出了它们的代谢特异性。这些细胞的特征是线粒体负荷增加和氧化应激，同时伴随着半胱氨酸代谢酶 3-巯基丙酮酸硫转移酶 (MPST) 的动员。利用患者肿瘤衍生细胞和组织类器官进行的功能测定，以及遗传和药理学操作证实，这些细胞依赖于增强的 ROS 产生和 MPST 活性来维持迁移能力。MPST 的作用涉及保护蛋白质半胱氨酸残基免受破坏性过度氧化。其敲低导致肿瘤负担减少，并且显著增加了小鼠的存活率。从对患者肿瘤的单细胞分析开始，我们的工作揭示了在异质基因组景观中维持的细胞恶性程度的代谢依赖性。
