Mass Spectrometry Imaging Combined with Metabolomics Revealing the Proliferative Effect of Environmental Pollutants on Multicellular Tumor Spheroids
Mass Spectrometry Imaging Combined with Metabolomics Revealing the Proliferative Effect of Environmental Pollutants on Multicellular Tumor Spheroids
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质谱成像结合代谢组学揭示环境污染物对多细胞肿瘤球体的增殖影响
DOI：
10.1021/acs.analchem.0c02025
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发表时间：
2020-08-18
影响因子：
7.4
通讯作者：
Cai, Zongwei
中科院分区：
文献类型：
--
作者：
Xie, Peisi;Liang, Xiaoping;Cai, Zongwei
多细胞肿瘤球体（MCTS）因其具有与实体肿瘤相似的生理学特征而在肿瘤研究中受到越来越多的关注。MCTS已被认为是一个有用的三维细胞模型，用于评估外源性分子对肿瘤进展的影响。然而，很少有人知道MCTS暴露于外源性分子后的代谢反应。在此，我们应用代谢组学结合MALDI-mass spectrometry imaging（MSI）来研究双酚S（BPS）处理的三维MDA-MB-231乳腺癌细胞球体的增殖。MSI数据显示，BPS是一种常见的环境污染物，在5 min内进入MCTS，并在4 h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种途径，包括嘌呤代谢和三羧酸循环。MSI结果显示，在细胞球体的增殖区分布着三种主要的能量供应代谢产物（ATP、ADP和AMP），进一步表明BPS暴露引起MDA-MB-231细胞球体的增殖反应。一个下调的代谢产物（黄嘌呤）与反应性氧化应激被发现定位于细胞球体的内部区域。这些MSI结果表明，细胞球体外层能量供应的增加可能是负责BPS诱导的增殖反应。总之，这种综合方法可能会提供一个更准确和直观的评估外源性分子对癌症进展的影响。
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.