State Key Laboratory of Environmental and Biological Analysis, Department of Chemistry, Hong Kong Baptist University, Hong Kong SAR, China.
School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou 510006, China.
Anal Chem. 2020 Aug 18;92(16):11341-11348. doi: 10.1021/acs.analchem.0c02025. Epub 2020 Jul 29.
Multicellular tumor spheroids (MCTS) have gained increasing attention in cancer research because they may closely mimic some physiological characteristics of solid tumors. MCTS have been considered as a useful three-dimensional cell model for evaluating the effect of exogenous molecules on tumor progression. However, little is known about the metabolic response in MCTS after exposure to exogenous molecules. Herein, we applied metabolomics combined with MALDI-mass spectrometry imaging (MSI) to investigate the proliferation of three-dimensional MDA-MB-231 breast cancer cell spheroids treated with bisphenol S (BPS). MSI data revealed that BPS, a common environmental contaminant, penetrated MCTS in 5 min and gradually localized in the core of MCTS within 4 h. Metabolomic data demonstrated that BPS exposure induced significant changes in the levels of 28 metabolites that are involved in several pathways, including purine metabolism and the tricarboxylic acid cycle. The MSI results showed that three upregulated metabolites (ATP, ADP, and AMP) acting major roles in energy supply distributed in the proliferative zone of cell spheroids, further indicating the proliferative response of MDA-MB-231 cell spheroids caused by BPS exposure. One downregulated metabolite (xanthine) associated with reactive oxidative stress was found to localize toward the inner region of cell spheroids. These MSI results demonstrated that the increase of energy supply in the outer layer of cell spheroids might be responsible for BPS-induced proliferative response. Taken together, this integrated method might offer a more accurate and intuitive assessment for the effect of exogenous molecules on cancer progression.
多细胞肿瘤球（MCTS）在癌症研究中受到越来越多的关注，因为它们可能更接近实体瘤的一些生理特征。MCTS 已被认为是评估外源性分子对肿瘤进展影响的有用的三维细胞模型。然而，对于外源性分子暴露后 MCTS 中的代谢反应知之甚少。在此，我们应用代谢组学结合 MALDI 质谱成像（MSI）来研究三种不同的 MDA-MB-231 乳腺癌细胞球在暴露于双酚 S（BPS）后的增殖情况。MSI 数据显示，双酚 S 是一种常见的环境污染物，可在 5 分钟内穿透 MCTS，并在 4 小时内逐渐定位于 MCTS 的核心。代谢组学数据表明，BPS 暴露诱导了 28 种代谢物水平的显著变化，这些代谢物参与了几个途径，包括嘌呤代谢和三羧酸循环。MSI 结果表明，三种上调的代谢物（ATP、ADP 和 AMP）在能量供应中起主要作用，分布在细胞球的增殖区，进一步表明 MDA-MB-231 细胞球因 BPS 暴露而发生的增殖反应。一个下调的代谢物（黄嘌呤）与活性氧化应激有关，发现它定位于细胞球的内部区域。这些 MSI 结果表明，细胞球外层的能量供应增加可能是 BPS 诱导增殖反应的原因。综上所述，这种综合方法可能为评估外源性分子对癌症进展的影响提供更准确、更直观的评估。
