title: A computational study of the Warburg effect identifies metabolic targets inhibiting cancer migration.
abstract: Over the last decade, the field of cancer metabolism has mainly focused on studying the role of tumorigenic metabolic rewiring in supporting cancer proliferation. Here, we perform the first genome-scale computational study of the metabolic underpinnings of cancer migration. We build genome-scale metabolic models of the NCI-60 cell lines that capture the Warburg effect (aerobic glycolysis) typically occurring in cancer cells. The extent of the Warburg effect in each of these cell line models is quantified by the ratio of glycolytic to oxidative ATP flux (AFR), which is found to be highly positively associated with cancer cell migration. We hence predicted that targeting genes that mitigate the Warburg effect by reducing the AFR may specifically inhibit cancer migration. By testing the anti-migratory effects of silencing such 17 top predicted genes in four breast and lung cancer cell lines, we find that up to 13 of these novel predictions significantly attenuate cell migration either in all or one cell line only, while having almost no effect on cell proliferation. Furthermore, in accordance with the predictions, a significant reduction is observed in the ratio between experimentally measured ECAR and OCR levels following these perturbations. Inhibiting anti-migratory targets is a promising future avenue in treating cancer since it may decrease cytotoxic-related side effects that plague current anti-proliferative treatments. Furthermore, it may reduce cytotoxic-related clonal selection of more aggressive cancer cells and the likelihood of emerging resistance.
authors.affiliation: The Blavatnik School of Computer Science, Tel-Aviv University, Tel-Aviv, Israel kerenyiz@post.tau.ac.il ruppin@post.tau.ac.il.
authors.forename: Keren
authors.initials: K
authors.lastname: Yizhak
authors.affiliation: Division of Toxicology, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands.
authors.forename: Sylvia E
authors.initials: SE
authors.lastname: Le Dévédec
authors.affiliation: Division of Toxicology, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands.
authors.forename: Vasiliki Maria
authors.initials: VM
authors.lastname: Rogkoti
authors.affiliation: Gene Expression Analysis Laboratory, Cancer Research UK, London Research Institute, London, UK.
authors.forename: Franziska
authors.initials: F
authors.lastname: Baenke
authors.affiliation: Laboratory Genetic Metabolic Diseases, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Vincent C
authors.initials: VC
authors.lastname: de Boer
authors.affiliation: MRC Cancer Unit, Hutchison/MRC Research Centre, University of Cambridge, Cambridge, UK.
authors.forename: Christian
authors.initials: C
authors.lastname: Frezza
authors.affiliation: Gene Expression Analysis Laboratory, Cancer Research UK, London Research Institute, London, UK.
authors.forename: Almut
authors.initials: A
authors.lastname: Schulze
authors.affiliation: Division of Toxicology, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands.
authors.forename: Bob
authors.initials: B
authors.lastname: van de Water
authors.affiliation: The Blavatnik School of Computer Science, Tel-Aviv University, Tel-Aviv, Israel The Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel kerenyiz@post.tau.ac.il ruppin@post.tau.ac.il.
authors.forename: Eytan
authors.initials: E
authors.lastname: Ruppin
mesh_terms: D001943:Breast Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D019295:Computational Biology / Q000379:methods*; D020868:Gene Silencing; D006019:Glycolysis; D006801:Humans; D019344:Lactic Acid / Q000378:metabolism; D008175:Lung Neoplasms / Q000378:metabolism*; D008954:Models, Biological; D034741:RNA, Small Interfering / Q000235:genetics
chemical_list: D034741:RNA, Small Interfering; D019344:Lactic Acid
keywords: cancer cell migration; cellular metabolism; genome‐scale metabolic modeling
references.citation: Nat Genet. 2011 May 29;43(7):656-62
references.pmid: 21623372
references.citation: Am J Physiol Cell Physiol. 2007 Jan;292(1):C125-36
references.pmid: 16971499
references.citation: Cancer Metab. 2013 Feb 04;1(1):9
references.pmid: 24280180
references.citation: Cancer Res. 2012 Nov 15;72(22):5712-20
references.pmid: 22986741
references.citation: Biochem Pharmacol. 2006 Mar 30;71(7):1026-35
references.pmid: 16329998
references.citation: Mol Syst Biol. 2013;9:649
references.pmid: 23511207
references.citation: Science. 2009 May 22;324(5930):1029-33
references.pmid: 19460998
references.citation: Breast Cancer Res. 2011 May 19;13(3):R52
references.pmid: 21595894
references.citation: Proc Natl Acad Sci U S A. 2007 Aug 7;104(32):13086-91
references.pmid: 17666531
references.citation: Proc Natl Acad Sci U S A. 2014 Mar 4;111(9):E866-75
references.pmid: 24550497
references.citation: Nat Cell Biol. 2008 Sep;10(9):1027-38
references.pmid: 19160483
references.citation: Nat Commun. 2012 Jul 03;3:929
references.pmid: 22760628
references.citation: Nat Rev Microbiol. 2004 Nov;2(11):886-97
references.pmid: 15494745
references.citation: Nat Cell Biol. 2005 Jun;7(6):581-90
references.pmid: 15895076
references.citation: Nat Biotechnol. 2012 Jul 10;30(7):671-8
references.pmid: 22781696
references.citation: Mol Syst Biol. 2014 Mar 19;10:721
references.pmid: 24646661
references.citation: Proc Natl Acad Sci U S A. 2005 Sep 20;102(38):13550-5
references.pmid: 16141321
references.citation: Proc Natl Acad Sci U S A. 2007 Feb 6;104(6):1777-82
references.pmid: 17267599
references.citation: Cell. 2011 Mar 4;144(5):646-74
references.pmid: 21376230
references.citation: Cell. 2013 Aug 1;154(3):651-63
references.pmid: 23911327
references.citation: Science. 2012 May 4;336(6081):601-4
references.pmid: 22556256
references.citation: Cell. 1999 Oct 1;99(1):23-33
references.pmid: 10520991
references.citation: Proc Natl Acad Sci U S A. 2005 Mar 8;102(10):3738-43
references.pmid: 15701700
references.citation: Science. 2012 May 25;336(6084):1040-4
references.pmid: 22628656
references.citation: Cancer Res. 2008 Feb 15;68(4):989-97
references.pmid: 18281472
references.citation: PLoS Comput Biol. 2012;8(5):e1002518
references.pmid: 22615553
references.citation: Mol Syst Biol. 2007;3:135
references.pmid: 17882155
references.citation: PLoS Comput Biol. 2010 Jul 15;6(7):e1000859
references.pmid: 20657658
references.citation: Cancer Res. 2011 Nov 15;71(22):6921-5
references.pmid: 22084445
references.citation: Nat Genet. 2000 Mar;24(3):236-44
references.pmid: 10700175
references.citation: Science. 2003 Dec 5;302(5651):1704-9
references.pmid: 14657486
references.citation: Cancer Res. 2002 Nov 15;62(22):6674-81
references.pmid: 12438266
references.citation: Nat Biotechnol. 2008 Sep;26(9):1003-10
references.pmid: 18711341
references.citation: Nat Commun. 2013;4:2632
references.pmid: 24153335
references.citation: Eur J Cancer. 2004 Jul;40(10):1502-8
references.pmid: 15196533
references.citation: Proc Natl Acad Sci U S A. 2012 Feb 14;109(7):2678-83
references.pmid: 22308420
references.citation: Proc Natl Acad Sci U S A. 2010 Oct 12;107(41):17845-50
references.pmid: 20876091
references.citation: Mol Syst Biol. 2011 Jun 21;7:501
references.pmid: 21694718
references.citation: Mol Syst Biol. 2011 Jul 19;7:515
references.pmid: 21772263
references.citation: J Clin Oncol. 2009 Jun 10;27(17):2809-15
references.pmid: 19380452
references.citation: Methods Mol Biol. 2011;769:435-48
references.pmid: 21748693
references.citation: Nat Biotechnol. 2010 Dec;28(12):1279-85
references.pmid: 21102456
references.citation: Nature. 2011 Aug 17;477(7363):225-8
references.pmid: 21849978
references.citation: Mol Syst Biol. 2010 Sep 7;6:411
references.pmid: 20823849
references.citation: PLoS Genet. 2008 Nov;4(11):e1000287
references.pmid: 19043577
references.citation: Mol Syst Biol. 2009;5:320
references.pmid: 19888215
references.citation: Nature. 2011 Aug 18;476(7360):346-50
references.pmid: 21760589
references.citation: PLoS Comput Biol. 2011 Mar;7(3):e1002018
references.pmid: 21423717
references.citation: Curr Opin Pharmacol. 2013 Oct;13(5):778-85
references.pmid: 23731523
references.citation: Biotechnol Bioeng. 2003 Dec 20;84(6):647-57
references.pmid: 14595777
references.citation: Bioinformatics. 2011 Feb 15;27(4):541-7
references.pmid: 21172910
references.citation: Nature. 2004 May 6;429(6987):92-6
references.pmid: 15129285
references.citation: Genome Res. 2004 Nov;14(11):2367-76
references.pmid: 15520298
references.citation: Nature. 2012 Apr 18;486(7403):346-52
references.pmid: 22522925
references.citation: Science. 1956 Feb 24;123(3191):309-14
references.pmid: 13298683