Alexei Vazquez - Mathematical Models of Metabolism

Introduction

vazquez

Metabolism is essential for life and its alteration is implicated in multiple human diseases. The transformation from a normal cell to a cancerous one requires metabolic changes to fuel the high metabolic demands of cancer cells, including but not limited to cell proliferation and cell migration. In recent years there have been a number of new discoveries connecting known aberrations in oncogenic and tumour suppressor pathways with metabolic alterations required to sustain cell proliferation and migration. However, an understanding of the selective advantage of these metabolic alterations is still lacking.

Our group investigates cancer metabolism from an evolutionary viewpoint. We hypothesise that, given specific microenvironmental conditions and metabolic constraints, there is an optimal mode of cell metabolism required to achieve a particular metabolic objective (e.g. energy production, cell proliferation). This metabolic mode will offer an evolutionary advantage and therefore will be selected for during the time course of cancer development. First, we aim to uncover the metabolic objectives and metabolic constraints upon which natural selection is acting. Second, we aim to determine which known (and yet to be discovered) molecular alterations are driving the deterministic or stochastic occurrence of the optimal metabolic modes.

Specific projects:

  • Molecular crowding is a major constraint acting on cell metabolism: The Warburg effect is the optimal mode of energy metabolism under nutrient abundance and molecular crowding [1,3]
  • Proliferation and tissue remodelling are two main metabolic objectives of cancer: Proliferation and tissue remodelling are major drivers of the gene expression patterns of cancer tissues and they determine cancer subtypes with significant survival differences [2]
  • Metabolic response to drugs targeting cancer metabolism: the response or resistance to a drug targeting cancer metabolism is determined by the current metabolic state [4,5]

Lab Report

 icon Vazquez Lab Report

Key Publications

Burgos-Barragan G, Wit N, Meiser J, Dingler FA, Pietzke M, Mulderrig L, Pontel LB, Rosado IV, Brewer TF, Cordell RL, Monks PS, Chang CJ, Vazquez A, Patel KJ. Mammals divert endogenous genotoxic formaldehyde into one-carbon metabolism. Nature 548: 549-54, 2017

Meiser J, Tumanov S, Maddocks O, Labuschagne CF, Athineos D, Van Den Broek N, Mackay GM, Gottlieb E, Blyth K, Vousden K, Kamphorst JJ, Vazquez A. Serine one-carbon catabolism with formate overflow. Science Advances 2: e1601273, 2016

Markert EK, Levine AJ, Vazquez A. Proliferation and tissue remodeling in cancer: the hallmarks revisited. Cell Death and Disease 3: e397, 2012

Vazquez A, Markert EK, Oltvai ZN. Serine biosynthesis with one carbon catabolism and the glycine cleavage system represents a novel pathway for ATP generation. PLoS One 6: e19538, 2011

Vazquez A, Liu J, Zhou Y, Oltvai ZN. Catabolic efficiency of aerobic glycolysis: The Warburg effect revisited. BMC Syst Biol 4: 58, 2010

Biography

Education and qualifications

2002: PhD, Statistical and Biological Physics, International School of Advanced Studies, Italy
1997: MSc, Physics, University of Havana, Cuba
1995: BSc, Physics, University of Havana, Cuba

Appointments

2014-present: Junior Group Leader, CRUK Beatson Institute, Glasgow
2009-2014: Assistant Professor, Rutgers Cancer Institute of New Jersey, USA
2006-2009: Member, Institute for Advanced Study, Princeton, USA
2002-2006: Postdoctoral Fellow with Albert-Laszlo Barabasi, University of Notre Dame, USA

Honours and awards

Rutgers Cancer Institute of New Jersey Award in Breast Cancer Research, 2014
Cuban Physical Society Prize to Young Physicists, 1996

Recent Publications

2017

Burgos-Barragan G, Wit N, Meiser J, Dingler FA, Pietzke M, Mulderrig L, Pontel LB, Rosado IV, Brewer TF, Cordell RL, Monks PS, Chang CJ, Vazquez A, Patel KJ. Mammals divert endogenous genotoxic formaldehyde into one-carbon metabolism. Nature 548: 549-54, 2017

Dolfi SC, Medina DJ, Kareddula A, Paratala B, Rose A, Dhami J, Chen S, Ganesan S, Mackay G, Vazquez A, Hirshfield KM (2017) Riluzole exerts distinct antitumor effects from a metabotropic glutamate receptor 1-specific inhibitor on breast cancer cells. Oncotarget, in press

Bulusu V, Tumanov S, Michalopoulou E, van den Broek NJ, Mackay G, Nixon C, Dhayade S, Schug ZT, Vande Voorde J, Blyth K, Gottlieb E, Vazquez A, Kamphorst JJ. Acetate recapturing by nuclear acetyl-CoA synthetase 2 prevents loss of histone acetylation during oxygen and serum limitation. Cell Reports 18: 647-58, 2017

2016

Meiser J, Tumanov S, Maddocks O, Labuschagne CF, Athineos D, Van Den Broek N, Mackay GM, Gottlieb E, Blyth K, Vousden K, Kamphorst JJ, Vazquez A. Serine one-carbon catabolism with formate overflow. Science Advances 2: e1601273, 2016

Vazquez A, Oltvai ZN. Macromolecular crowding explains overflow metabolism in cells. Sci Rep 6: 31007, 2016

Hirshfield KM, Tolkunov D, Zhong H, Ali SM, Stein MN, Murphy S, Vig H, Vazquez A, Glod J, Moss RA, Belyi V, Chan CS, Chen S, Goodell L, Foran D, Yelensky R, Palma NA, Sun JX, Miller VA, Stephens PJ, Ross JS, Kaufman H, Poplin E, Mehnert J, Tan AR, Bertino JR, Aisner J, DiPaola RS, Rodriguez-Rodriguez L, Ganesan S. Clinical actionability of comprehensive genomic profiling for management of rare or refractory cancers. Oncologist 2016 Aug 26. pii: theoncologist.2016-0049, 2016

Meiser J, Vazquez A. Give it or take it: The flux of one-carbon in cancer cells. FEBS J 283: 3695-704, 2016

Vazquez A, Kamphorst JJ, Markert EK, Schug ZT, Tardito S, Gottlieb E. Cancer metabolism at a glance. J Cell Sci 129: 3367-73, 2016

2015

Vazquez A. Limits of aerobic metabolism in cancer cells. bioRxiv doi: http://dx.doi.org/10.1101/020461

Tedeschi PM, Johnson-Farley N, Lin H, Shelton LM, Ooga T, Mackay G, Van Den Broek N, Bertino JR, Vazquez A. Quantification of folate metabolism using transient metabolic flux analysis. Cancer & Metabolism 3: 6, 2015

Tedeschi PM, Vazquez A, Kerrigan JE, Bertino JR. Mitochondrial Methylene Tetrahydrofolate Dehydrogenase (MTHFD2) Overexpression is Associated with Tumor Cell Proliferation and is a Novel Target for Drug Development. Mol Cancer Res 13: 1361-6, 2015

Buescher JM, Antoniewicz MR, Boros LG, Burgess SC, Brunengraber H, Clish CB, DeBerardinis RJ, Feron O, Frezza C, Ghesquiere B, Gottlieb E, Hiller K, Jones RG, Kamphorst JJ, Kibbey RG, Kimmelman AC, Locasale JW, Lunt SY, Maddocks ODK, Malloy C, Metallo CM, Meuillet EJ, Munger J, Noh K, Rabinowitz JD, Ralser M, Sauer U, Stephanopoulos G, St-Pierre J, Tennant DA, Wittmann C, Vander Heiden M, Vazquez A, Vousden K, Young JD, Zamboni N, Fendt SM. A roadmap for interpreting 13C metabolite labeling patterns from cells. Current Opinion in Biotechnology 34: 189-201, 2015

2014

Cicchini M, Chakrabarti R, Kongara S, Price S, Nahar R, Lozy F, Zhong H, Vazquez A, Kang Y, Karantza V. Autophagy regulator BECN1 suppresses mammary tumorigenesis driven by WNT1 activation and following parity. Autophagy 2014; 10:1–17.

Lozy F, Cai-McRae X, Teplova I, Price S, Reddy A, Bhanot G, Ganesan S, Vazquez A, Karantza V. ERBB2 overexpression suppresses stress-induced autophagy and renders ERBB2-induced mammary tumorigenesis independent of monoallelic Becn1 loss. Autophagy 2014; 10:1-15.

Yu X, Narayanan S, Vazquez A, Carpizo DR. Small molecule compounds targeting the p53 pathway: are we finally making progress? Apoptosis 2014; 19:1055-1068.

2013

Vazquez A. Optimization of personalized therapies for anticancer treatment. BMC Syst Biol. 2013; 7:31.

Dolfi SC, Chan LL-Y, Qiu J, Tedeschi PM, Bertino JR, Hirshfield KM, Oltvai ZN, Vazquez A. The metabolic demands of cancer cells are coupled to their size and protein synthesis rates. Cancer & Metabolism 2013; 1:20.

Tedeschi PM, Markert EK, Gounder M, Lin H, Dvorzhinski D, Dolfi SC, Chan LY-Y, Qiu J, DiPaola RS, Hirshfield KM, Boros LG, Bertino JR, Oltvai ZN and Vazquez A. Contribution of serine, folate and glycine metabolism to the ATP, NADPH and purine requirements of cancer cells. Cell Death & Disease 2013; 4:e877.

Zhou Y, Vazquez A, Wise A, Warita T, Warita K, Bar-Joseph Z, Oltvai ZN. Carbon catabolite repression correlates with the maintenance of near invariant molecular crowding in proliferating E. coli cells. BMC Syst Biol 2013; 7:138.

Vazquez A. Metabolic States following accumulation of intracellular aggregates: implications for neurodegenerative diseases. PLoS One. 2013;8:e63822.

Kang W, Dipaola RS, Vazquez A. Inference of synergy/antagonism between anticancer drugs from the pooled analysis of clinical trials. BMC Med Res Methodol. 2013; 13:77.

Wuchty S, Vazquez A, Bozdag S and Bauer PO. Genome-wide associations of signaling pathways in glioblastoma multiforme. BMC Medical Genomics 2013; 6:11.

2012

Markert EK, Levine AJ and Vazquez A. Proliferation and tissue remodeling in cancer: the hallmarks revisited. Cell Death and Disease 2012; 3:e397.

Vazquez A, Tedeschi PM and Bertino JR. Over expression of the mitochondrial folate and glycine-serine pathway: a new determinant of methotrexate selectivity in tumors. Cancer Res 2013; 73:478-82.

Yu X, Vazquez A, Levine AJ and Carpizo DR. Allele-specific p53 mutant reactivation. Cancer Cell 2012; 21:614-625.

Lab Members

vazquez group

Post-docs

Johannes Meiser (Deutsche Forschungsgemeinschaft Fellowship)
Kristell Oizel
Matthias Pietzke

PhD Student

Silvia Halim

Research

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Seminars

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Find out more about our seminars including our Distinguished Seminar Programme.

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