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Quantitation of Endogenous Metabolites in Mouse Tumors Using Mass-Spectrometry Imaging
AstraZeneca, IMED Biotech Unit, Pathol Drug Safety & Metab, Darwin Bldg,Cambridge Sci Pk,Milton Rd, Cambridge CB4 0WG, Cambs, England;Sheffield Hallam Univ, Ctr Mass Spectrometry Imaging, Biomol Res Ctr, Sheffield S1 1WB, S Yorkshire, England.
Natl Ctr Excellence Mass Spectrometry Imaging NiC, Natl Phys Lab, Teddington TW11 0LW, Middx, England.
AstraZeneca, IMED Biotech Unit, Pathol Drug Safety & Metab, Darwin Bldg,Cambridge Sci Pk,Milton Rd, Cambridge CB4 0WG, Cambs, England.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
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2018 (English)In: Analytical Chemistry, ISSN 0003-2700, E-ISSN 1520-6882, Vol. 90, no 10, p. 6051-6058Article in journal (Refereed) Published
Abstract [en]

Described is a quantitative-mass-spectrometry-imaging (qMSI) methodology for the analysis of lactate and glutamate distributions in order to delineate heterogeneity among mouse tumor models used to support drug-discovery efficacy testing. We evaluate and report on preanalysis-stabilization methods aimed at improving the reproducibility and efficiency of quantitative assessments of endogenous molecules in tissues. Stability experiments demonstrate that optimum stabilization protocols consist of frozen-tissue embedding, post-tissue-sectioning desiccation, and storage at -80 degrees C of tissue sections sealed in vacuum-tight containers. Optimized stabilization protocols are used in combination with qMSI methodology for the absolute quantitation of lactate and glutamate in tumors, incorporating the use of two different stable-isotope-labeled versions of each analyte and spectral-clustering performed on each tissue section using k-means clustering to allow region-specific, pixel-by-pixel quantitation. Region-specific qMSI was used to screen different tumor models and identify a phenotype that has low lactate heterogeneity, which will enable accurate measurements of lactate modulation in future drug-discovery studies. We conclude that using optimized qMSI protocols, it is possible to quantify endogenous metabolites within tumors, and region-specific quantitation can provide valuable insight into tissue heterogeneity and the tumor microenvironment.

Place, publisher, year, edition, pages
AMER CHEMICAL SOC , 2018. Vol. 90, no 10, p. 6051-6058
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Analytical Chemistry
Identifiers
URN: urn:nbn:se:uu:diva-356451DOI: 10.1021/acs.analchem.7b05239ISI: 000432478600013PubMedID: 29668267OAI: oai:DiVA.org:uu-356451DiVA, id: diva2:1236292
Funder
Swedish Research Council, 2014-6215Swedish Foundation for Strategic Research , RIF14-0078AstraZenecaScience for Life Laboratory - a national resource center for high-throughput molecular bioscienceAvailable from: 2018-08-01 Created: 2018-08-01 Last updated: 2018-08-01Bibliographically approved

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Nilsson, AnnaAndrén, Per E.

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