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dc.contributor.authorIliopoulos, Othon
dc.contributor.authorKeibler, Mark Andrew
dc.contributor.authorWasylenko, Thomas Michael
dc.contributor.authorVander Heiden, Matthew G.
dc.contributor.authorStephanopoulos, Gregory
dc.contributor.authorKelleher, Joanne Keene
dc.date.accessioned2018-07-11T19:57:07Z
dc.date.available2018-07-11T19:57:07Z
dc.date.issued2016-08
dc.date.submitted2016-05
dc.identifier.issn2049-3002
dc.identifier.urihttp://hdl.handle.net/1721.1/116916
dc.description.abstractBackground: The study of cancer metabolism has been largely dedicated to exploring the hypothesis that oncogenic transformation rewires cellular metabolism to sustain elevated rates of growth and division. Intense examination of tumors and cancer cell lines has confirmed that many cancer-associated metabolic phenotypes allow robust growth and survival; however, little attention has been given to explicitly identifying the biochemical requirements for cell proliferation in a rigorous manner in the context of cancer metabolism. Results: Using a well-studied hybridoma line as a model, we comprehensively and quantitatively enumerate the metabolic requirements for generating new biomass in mammalian cells; this indicated a large biosynthetic requirement for ATP, NADPH, NAD+, acetyl-CoA, and amino acids. Extension of this approach to serine/glycine and glutamine metabolic pathways suggested lower limits on serine and glycine catabolism to supply one-carbon unit synthesis and significant availability of glutamine-derived carbon for biosynthesis resulting from nitrogen demands alone, respectively. We integrated our biomass composition results into a flux balance analysis model, placing upper bounds on mitochondrial NADH oxidation to simulate metformin treatment; these simulations reproduced several empirically observed metabolic phenotypes, including increased reductive isocitrate dehydrogenase flux. Conclusions: Our analysis clarifies the differential needs for central carbon metabolism precursors, glutamine-derived nitrogen, and cofactors such as ATP, NADPH, and NAD+, while also providing justification for various extracellular nutrient uptake behaviors observed in tumors. Collectively, these results demonstrate how stoichiometric considerations alone can successfully predict empirically observed phenotypes and provide insight into biochemical dynamics that underlie responses to metabolic perturbations.en_US
dc.description.sponsorshipNational Institutes of Health (U.S.) (Grant 1R01DK075850-01)en_US
dc.description.sponsorshipNational Institutes of Health (U.S.) (Grant 1R01CA160458-01A1)en_US
dc.publisherBioMed Central Ltden_US
dc.relation.isversionofhttp://dx.doi.org/10.1186/S40170-016-0156-6en_US
dc.rightsCreative Commons Attribution 4.0 International Licenseen_US
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en_US
dc.sourceBioMedCentralen_US
dc.titleMetabolic requirements for cancer cell proliferationen_US
dc.typeArticleen_US
dc.identifier.citationKeibler, Mark A. et al. “Metabolic Requirements for Cancer Cell Proliferation.” Cancer & Metabolism 4, 1 (August 2016): 16 © 2016 The Author(s)en_US
dc.contributor.departmentMassachusetts Institute of Technology. Department of Biologyen_US
dc.contributor.departmentMassachusetts Institute of Technology. Department of Chemical Engineeringen_US
dc.contributor.departmentKoch Institute for Integrative Cancer Research at MITen_US
dc.contributor.mitauthorKeibler, Mark Andrew
dc.contributor.mitauthorWasylenko, Thomas Michael
dc.contributor.mitauthorKelleher, Joanne K
dc.contributor.mitauthorVander Heiden, Matthew G.
dc.contributor.mitauthorStephanopoulos, Gregory
dc.relation.journalCancer & Metabolismen_US
dc.eprint.versionFinal published versionen_US
dc.type.urihttp://purl.org/eprint/type/JournalArticleen_US
eprint.statushttp://purl.org/eprint/status/PeerRevieweden_US
dc.date.updated2018-07-11T17:45:37Z
dspace.orderedauthorsKeibler, Mark A.; Wasylenko, Thomas M.; Kelleher, Joanne K.; Iliopoulos, Othon; Vander Heiden, Matthew G.; Stephanopoulos, Gregoryen_US
dspace.embargo.termsNen_US
dc.identifier.orcidhttps://orcid.org/0000-0002-5410-6543
dc.identifier.orcidhttps://orcid.org/0000-0002-8676-5738
dc.identifier.orcidhttps://orcid.org/0000-0002-6702-4192
dc.identifier.orcidhttps://orcid.org/0000-0001-6909-4568
mit.licensePUBLISHER_CCen_US


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