Mass Spectrometry Imaging Combined with Metabolomics Revealing the Proliferative Effect of Environmental Pollutants on Multicellular Tumor Spheroids

Abstract

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 threedimensional 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.

Hydralazine as a Versatile and Universal Matrix for High-Molecular Coverage and Dual-Polarity Matrix-Assisted Laser Desorption/Ionization Mass Spectrometry Imaging

“…Matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI) is an attractive technique used for targeted and untargeted spatial imaging of various biomolecules in tissues. − The application spans from medical and biomedical research studies, clinicopathology imaging to drug research and development. ,− Building on the pioneering studies of Karas et al and Tanaka et al in MALDI MS, this technology has improved markedly from its inception with the introduction of high-mass and high-spatial resolution equipment capable of 1–10 μm resolution. , The upsurge of this label-free technique has been used for both qualitative and quantitative analyses of diverse compounds ranging from small molecule metabolites to peptides and proteins, , as well as drugs , and environmental pollutants in various complex samples. MALDI MSI has become a powerful molecular imaging tool to bridge the gap between the histomorphology and individual molecules in the micro/nanoscale and provides new insights into the tissue-specific metabolism in the occurrence and development of various diseases.…”

Development of a Matrix Sublimation Device with Controllable Crystallization Temperature for MALDI Mass Spectrometry Imaging

“…Another typical application of MALDI-MSI is the analysis of exogenous components in various tissues. − It has been reported that the persistent organic pollutant PFOSs could induce oxidative damage to the kidneys of mice . Herein, the mouse kidney deposited with PFHxS/PFOSs via the dry droplet method was used as a model to assess the sublimator for MALDI-MSI.…”

The application of mass spectrometry imaging in traditional Chinese medicine: a review

“…Besides, MSI makes it possible to look into diagnosis and prognosis of disease in an innovative way [ 20 , 21 ]. Data generated from MSI could provide information of metabolic response in tumor tissues, thus enabling a deeper exploration of tumor microenvironment [ 22 , 23 ]. In the past few years, researchers have attempted to observe the localization of endogenous metabolites in plant tissues using MSI [ 24 ].…”