Abstract
The metabolic activity of a mammalian cell changes dynamically over time and is tied to the changing metabolic demands of cellular processes such as cell differentiation and proliferation. While experimental tools like time-course metabolomics and flux tracing can measure the dynamics of a few pathways, they are unable to infer fluxes at the whole network level. To address this limitation, we have developed the Dynamic Flux Activity (DFA) algorithm, a genome-scale modeling approach that uses time-course metabolomics to predict dynamic flux rewiring during transitions between metabolic states. This chapter provides a protocol for applying DFA to characterize the dynamic metabolic activity of various cancer cell lines.
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References
Luengo A, Gui DY, Vander Heiden MG (2017) Targeting metabolism for cancer therapy. Cell Chem Biol 24(9):1161–1180. https://doi.org/10.1016/j.chembiol.2017.08.028
Saa PA, Nielsen LK (2017) Formulation, construction and analysis of kinetic models of metabolism: a review of modelling frameworks. Biotechnol Adv 35(8):981–1003. https://doi.org/10.1016/J.BIOTECHADV.2017.09.005
Nilsson A, Nielsen J, Palsson BO (2017) Commentary metabolic models of protein allocation call for the kinetome. Cell Syst 5:538–541. https://doi.org/10.1016/j.cels.2017.11.013
Orth JD, Thiele I, Palsson BØ (2010) What is flux balance analysis? Nat Biotechnol 28(3):245–248. https://doi.org/10.1038/nbt.1614
O’Brien EJ, Monk JM, Palsson BO (2015) Using genome-scale models to predict biological capabilities. Cell 161(5):971–987. https://doi.org/10.1016/j.cell.2015.05.019
Uhlén M, Hallström BM, Lindskog C, Mardinoglu A, Pontén F, Nielsen J (2016) Transcriptomics resources of human tissues and organs. Mol Syst Biol 12(4):862. https://doi.org/10.15252/msb.20155865
Chandrasekaran S, Zhang J, Sun Z, Zhang L, Ross CA, Huang Y-C et al (2017) Comprehensive mapping of pluripotent stem cell metabolism using dynamic genome-scale network modeling. Cell Rep 21(10):2965–2977. https://doi.org/10.1016/J.CELREP.2017.07.048
Bordbar A, Yurkovich JT, Paglia G, Rolfsson O, Sigurjónsson ÓE, Palsson BO (2017) Elucidating dynamic metabolic physiology through network integration of quantitative time-course metabolomics. Sci Rep 7:46249
Heirendt L, Arreckx S, Pfau T, Mendoza SN, Richelle A, Heinken A et al (2017) Creation and analysis of biochemical constraint-based models: the COBRA Toolbox v3.0. http://arxiv.org/abs/1710.04038
Zielinski DC, Jamshidi N, Corbett AJ, Bordbar A, Thomas A, Palsson BO (2017) Systems biology analysis of drivers underlying hallmarks of cancer cell metabolism. Sci Rep 7:41241
King ZA, Dräger A, Ebrahim A, Sonnenschein N, Lewis NE, Palsson BO (2015) Escher: a web application for building, sharing, and embedding data-rich visualizations of biological pathways. PLoS Comput Biol 11(8):e1004321. https://doi.org/10.1371/journal.pcbi.1004321
Jain M, Nilsson R, Sharma S, Madhusudhan N, Kitami T, Souza AL et al (2012) Metabolite profiling identifies a key role for glycine in rapid cancer cell proliferation. Science 336(6084):1040–1044. https://doi.org/10.1126/science.1218595
Yizhak K, Gaude E, Le Dévédec S, Waldman YY, Stein GY, van de Water B et al (2014) Phenotype-based cell-specific metabolic modeling reveals metabolic liabilities of cancer. Elife 3. https://doi.org/10.7554/eLife.03641
Lewis NE, Hixson KK, Conrad TM, Lerman JA, Charusanti P, Polpitiya AD et al (2010) Omic data from evolved E. coli are consistent with computed optimal growth from genome-scale models. Mol Syst Biol 6:390. https://doi.org/10.1038/msb.2010.47
Chong J, Soufan O, Li C, Caraus I, Li S, Bourque G et al (2018) MetaboAnalyst 4.0: towards more transparent and integrative metabolomics analysis. Nucleic Acids Res 46(W1):W486–W494. https://doi.org/10.1093/nar/gky310
Shen F, Boccuto L, Pauly R, Srikanth S, Chandrasekaran S (2019) Genome-scale network model of metabolism and histone acetylation reveals metabolic dependencies of histone deacetylase inhibitors. Genome Biol 20(1):49
Chandrasekaran S, Price ND (2010) Probabilistic integrative modeling of genome-scale metabolic and regulatory networks in Escherichia coli and Mycobacterium tuberculosis. Proc Natl Acad Sci U S A 107(41):17845–17850. https://doi.org/10.1073/pnas.1005139107
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Campit, S., Chandrasekaran, S. (2020). Inferring Metabolic Flux from Time-Course Metabolomics. In: Nagrath, D. (eds) Metabolic Flux Analysis in Eukaryotic Cells. Methods in Molecular Biology, vol 2088. Humana, New York, NY. https://doi.org/10.1007/978-1-0716-0159-4_13
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DOI: https://doi.org/10.1007/978-1-0716-0159-4_13
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