State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Key Laboratory of Mass Spectrometry Imaging and Metabolomics (Minzu University of China), National Ethnic Affairs Commission, Beijing, China.
Rapid Commun Mass Spectrom. 2024 Jan 30;38(2):e9670. doi: 10.1002/rcm.9670.
Multicellular tumor spheroids (MCTSs) that reconstitute the metabolic characteristics of in vivo tumor tissue may facilitate the discovery of molecular biomarkers and effective anticancer therapies. However, little is known about how cancer cells adapt their metabolic changes in complex three-dimensional (3D) microenvironments. Here, using the two-dimensional (2D) cell model as control, the metabolic phenotypes of glioma U87MG multicellular tumor spheroids were systematically investigated based on static metabolomics and dynamic fluxomics analysis.
A liquid chromatography-mass spectrometry-based global metabolomics and lipidomics approach was adopted to survey the cellular samples from 2D and 3D culture systems, revealing marked molecular differences between them. Then, by means of metabolomic pathway analysis, the metabolic pathways altered in glioma MCTSs were found using C -glucose as a tracer to map the metabolic flux of glycolysis, the tricarboxylic acid (TCA) cycle, de novo nucleotide synthesis, and de novo lipid biosynthesis in the MCTS model.
We found nine metabolic pathways as well as glycerolipid, glycerophospholipid and sphingolipid metabolism to be predominantly altered in glioma MCTSs. The reduced nucleotide metabolism, amino acid metabolism and glutathione metabolism indicated an overall lower cellular activity in MCTSs. Through dynamic fluxomics analysis in the MCTS model, we found that cells cultured in MCTSs exhibited increased glycolysis activity and de novo lipid biosynthesis activity, and decreased the TCA cycle and de novo purine nucleotide biosynthesis activity.
Our study highlights specific, altered biochemical pathways in MCTSs, emphasizing dysregulation of energy metabolism and lipid metabolism, and offering novel insight into metabolic events in glioma MCTSs.
重建体内肿瘤组织代谢特征的多细胞肿瘤球体（MCTS）有助于发现分子生物标志物和有效的抗癌疗法。然而，对于癌细胞如何在复杂的三维（3D）微环境中适应代谢变化，人们知之甚少。在这里，我们以二维（2D）细胞模型作为对照，基于静态代谢组学和动态通量组学分析，系统研究了胶质瘤 U87MG 多细胞肿瘤球体的代谢表型。
采用基于液相色谱-质谱的全局代谢组学和脂质组学方法，对 2D 和 3D 培养系统中的细胞样本进行了调查，揭示了它们之间明显的分子差异。然后，通过代谢组学途径分析，使用 C-葡萄糖作为示踪剂，发现胶质瘤 MCTS 中改变的代谢途径，以映射 MCTS 模型中糖酵解、三羧酸（TCA）循环、从头核苷酸合成和从头脂质生物合成的代谢通量。
我们发现了九个代谢途径以及甘油磷脂、甘油磷酯和鞘脂代谢在胶质瘤 MCTS 中主要发生改变。核苷酸代谢、氨基酸代谢和谷胱甘肽代谢的减少表明 MCTS 中的细胞活性总体较低。通过 MCTS 模型中的动态通量组学分析，我们发现培养在 MCTS 中的细胞表现出增加的糖酵解活性和从头脂质生物合成活性，并且降低了 TCA 循环和从头嘌呤核苷酸生物合成活性。
我们的研究强调了 MCTS 中特定的、改变的生化途径，强调了能量代谢和脂质代谢的失调，并为胶质瘤 MCTS 中的代谢事件提供了新的见解。
