Eyal Gottlieb - Apoptosis and Tumour Metabolism

Introduction

gottlieb e 2016

Cancer cells must duplicate their genome, synthesise proteins and lipids, and assemble these components to form daughter cells. These activities require increased uptake of nutrients to be used as biosynthetic precursors and energy. However, rapid tumour growth surpasses the required blood supply and exposes cancer cells to conditions of metabolic stress. Therefore, cancer cells undergo many metabolic changes that support growth and survival.

My laboratory combines analytical chemistry (metabolomics), cell biology, and biochemical approaches to study metabolic transformation. These technologies are not only important for understanding the basic biochemistry of cancer cells but they can inform us on future clinical management of cancer and may lead to new therapeutic approaches to target cancer-specific metabolic pathways.

Lab Report

Key Publications

Cardaci S, Zheng L, MacKay G, van den Broek NJ, MacKenzie ED, Nixon C, Stevenson D, Tumanov S, Bulusu V, Kamphorst JJ, Vazquez A, Fleming S, Schiavi F, Kalna G, Blyth K, Strathdee D, Gottlieb E. Pyruvate carboxylation enables growth of SDH-deficient cells by supporting aspartate biosynthesis. Nat Cell Biol 17: 1317-26, 2015

Schug ZT, Peck B, Jones DT, Zhang Q, Grosskurth S, Alam IS, Goodwin LM, Smethurst E, Mason S, Blyth K, McGarry L, James D, Shanks E, Kalna G, Saunders RE, Jiang M, Howell M, Lassailly F, Thin MZ, Spencer-Dene B, Stamp G, van den Broek NJ, Mackay G, Bulusu V, Kamphorst JJ, Tardito S, Strachan D, Harris AL, Aboagye EO, Critchlow SE, Wakelam MJ, Schulze A, Gottlieb E. Acetyl-CoA synthetase 2 promotes acetate utilization and maintains cancer cell growth under metabolic stress. Cancer Cell 27: 57-71, 2015

Chaneton B, Hillmann P, Zheng L, Martin AC, Maddocks OD, Chokkathukalam A, Coyle JE, Jankevics A, Holding FP, Vousden KH, Frezza C, O'Reilly M, Gottlieb E. Serine is a natural ligand and allosteric activator of pyruvate kinase M2. Nature 491: 458-62, 2012

Frezza C, Zheng L, Folger O, Rajagopalan KN, Mackenzie ED, Jerby L, Micaroni M, Chaneton B, Adam J, Hedley A, Kalna G, Tomlinson IP, Pollard PJ, Watson DG, Deberardinis RJ, Shlomi T, Ruppin E, Gottlieb E (2011). Haem oxygenase is synthetically lethal with the tumour suppressor fumarate hydratase. Nature 477(7363): 225-8, 2011

Selak MA, Armour SM, MacKenzie ED, Boulahbel H, Watson DG, Mansfield KD, Yi P, Simon MC, Thompson CB, Gottlieb E. Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-α prolyl hydroxylase. Cancer Cell 7: 77-85, 2005

Biography

Education and qualifications

1999: PhD, Weizmann Institute of Science, Israel, Supervisor Moshe Oren
1992: MSc, Weizmann Institute of Science, Israel, Supervisor Moshe Oren
1990: BSc, Hebrew University, Israel

Appointments

2003-present: Group Leader, CRUK Beatson Institute, Glasgow
2009-present: Professor, University of Glasgow
2007-2009: Reader, University of Glasgow
1999-2003: Postdoctoral Fellow with Craig Thompson, University of Pennsylvania, Philadelphia, USA
1998-1999: Postdoctoral Fellow with Craig Thompson, University of Chicago, USA

Honours and awards

Leukemia and Lymphoma Society Special Fellowship, 2001
EMBO Long-Term Fellowship, 1998

Recent Publications

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

Tumanov S, Bulusu V, Gottlieb E, Kamphorst JJ. A rapid method for quantifying free and bound acetate based on alkylation and GC-MS analysis. Cancer & Metabolism 4: 17, 2016

Kamphorst JJ, Gottlieb E. Cancer metabolism: Friendly neighbours feed tumour cells. Nature 536: 401-402, 2016

Sciacovelli M, Gonçalves E, Johnson TI, Zecchini VR, da Costa AS, Gaude E, Drubbel AV, Theobald SJ, Abbo SR, Tran MG, Rajeeve V, Cardaci S, Foster S, Yun H, Cutillas P, Warren A, Gnanapragasam V, Gottlieb E, Franze K, Huntly B, Maher ER, Maxwell PH, Saez-Rodriguez J, Frezza C. Fumarate is an epigenetic modifier that elicits epithelial-to-mesenchymal transition. Nature. 2016 Aug 31. doi: 10.1038/nature19353. [Epub ahead of print]

Schug ZT, Vande Voorde J, Gottlieb E.The metabolic fate of acetate in cancer. Nat Rev Cancer. 2016 Aug 26. doi: 10.1038/nrc.2016.87. [Epub ahead of print]

2015

Baenke F, Chaneton B, Smith M, Van Den Broek N, Hogan K, Tang H, Viros A, Martin M, Galbraith L, Girotti MR, Dhomen N, Gottlieb E, Marais R. Resistance to BRAF inhibitors induces glutamine dependency in melanoma cells. Mol Oncol 2015. doi: 10.1016/j.molonc.2015.08.003. Epub 2015 Aug 20

Cadalbert LC, Ghaffar FN, Stevenson D, Bryson S, Vaz FM, Gottlieb E, Strathdee D. Mouse Tafazzin Is Required for Male Germ Cell Meiosis and Spermatogenesis. PLoS One 10: e0131066, 2015

Cardaci S, Zheng L, MacKay G, van den Broek NJ, MacKenzie ED, Nixon C, Stevenson D, Tumanov S, Bulusu V, Kamphorst JJ, Vazquez A, Fleming S, Schiavi F, Kalna G, Blyth K, Strathdee D, Gottlieb E. Pyruvate carboxylation enables growth of SDH-deficient cells by supporting aspartate biosynthesis. Nat Cell Biol 17: 1317-26, 2015

Fack F, Espedal H, Keunen O, Golebiewska A, Obad N, Harter PN, Mittelbronn M, Bahr O, Weyerbrock A, Stuhr L, Miletic H, Sakariassen PO, Stieber D, Rygh CB, Lund-Johansen M, Zheng L, Gottlieb E, Niclou SP, Bjerkvig R. Bevacizumab treatment induces metabolic adaptation toward anaerobic metabolism in glioblastomas. Acta Neuropathol 129: 115-31, 2015

Kluckova K, Sticha M, Cerny J, Mracek T, Dong L, Drahota Z, Gottlieb E, Neuzil J, Rohlena J. Ubiquinone-binding site mutagenesis reveals the role of mitochondrial complex II in cell death initiation. Cell Death Dis 6: e1749, 2015

Mackay GM, Zheng L, van den Broek NJ, Gottlieb E. Analysis of Cell Metabolism Using LC-MS and Isotope Tracers. Methods Enzymol 561: 171-96, 2015

Patella F, Schug ZT, Persi E, Neilson LJ, Erami Z, Avanzato D, Maione F, Hernandez-Fernaud JR, Mackay G, Zheng L, Reid S, Frezza C, Giraudo E, Fiorio Pla A, Anderson K, Ruppin E, Gottlieb E, Zanivan S. Proteomics-based metabolic modeling reveals that fatty acid oxidation (FAO) controls endothelial cell (EC) permeability. Mol Cell Proteomics 14: 621-34, 2015

Schug ZT, Peck B, Jones DT, Zhang Q, Grosskurth S, Alam IS, Goodwin LM, Smethurst E, Mason S, Blyth K, McGarry L, James D, Shanks E, Kalna G, Saunders RE, Jiang M, Howell M, Lassailly F, Thin MZ, Spencer-Dene B, Stamp G, van den Broek NJ, Mackay G, Bulusu V, Kamphorst JJ, Tardito S, Strachan D, Harris AL, Aboagye EO, Critchlow SE, Wakelam MJ, Schulze A, Gottlieb E. Acetyl-CoA synthetase 2 promotes acetate utilization and maintains cancer cell growth under metabolic stress. Cancer Cell 27: 57-71, 2015

Zheng L, Cardaci S, Jerby L, MacKenzie ED, Sciacovelli M, Johnson TI, Gaude E, King A, Leach JD, Edrada-Ebel R, Hedley A, Morrice NA, Kalna G, Blyth K, Ruppin E, Frezza C, Gottlieb E. Fumarate induces redox-dependent senescence by modifying glutathione metabolism. Nat Commun 6: 6001, 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 OD, 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 MG, Vazquez A, Vousden K, Young JD, Zamboni N, Fendt SM. A roadmap for interpreting C metabolite labeling patterns from cells. Curr Opin Biotechnol 34: 189-201, 2015

Nowicki S, Gottlieb E. Oncometabolites: tailoring our genes. FEBS J 282: 2796-805, 2015

Olivares O, Dabritz JH, King A, Gottlieb E, Halsey C. Research into Cancer Metabolomics: Towards a Clinical Metamorphosis. Semin Cell Dev Biol 2015. doi: 10.1016/j.semcdb.2015.09.008. Epub 2015 Sep 11

Yizhak K, Chaneton B, Gottlieb E, Ruppin E. Modeling cancer metabolism on a genome scale. Mol Syst Biol 11: 817, 2015

2014

Jerby-Arnon L, Pfetzer N, Waldman YY, McGarry L, James D, Shanks E, Seashore-Ludlow B, Weinstock A, Geiger T, Clemons PA, Gottlieb E, Ruppin E. Predicting cancer-specific vulnerability via data-driven detection of synthetic lethality. Cell 158: 1199-209, 2014

Oburoglu L, Tardito S, Fritz V, de Barros SC, Merida P, Craveiro M, Mamede J, Cretenet G, Mongellaz C, An X, Klysz D, Touhami J, Boyer-Clavel M, Battini JL, Dardalhon V, Zimmermann VS, Mohandas N, Gottlieb E, Sitbon M, Kinet S, Taylor N. Glucose and Glutamine Metabolism Regulate Human Hematopoietic Stem Cell Lineage Specification. Cell Stem Cell 15: 169-84, 2014

Witney TH, Pisaneschi F, Alam IS, Trousil S, Kaliszczak M, Twyman F, Brickute D, Nguyen QD, Schug Z, Gottlieb E, Aboagye EO. Preclinical Evaluation of 3-18F-Fluoro-2,2-Dimethylpropionic Acid as an Imaging Agent for Tumor Detection. J Nucl Med 55: 1506-12, 2014

2013

Kaplon J, Zheng L, Meissl K, Chaneton B, Selivanov VA, MacKay G, van der Burg SH, Verdegaal EME, Cascante M, Shlomi T, Gottlieb E*, Peeper DS*. A critical role for the mitochondrial gatekeeper pyruvate dehydrogenase in oncogene-induced senescence. Nature, in press 2013 (*Equal Contribution)

Zheng L, MacKenzie ED, Karim SA, Hedley A, Blyth K, Kalna G, Watson DG, Szlosarek P, Frezza C, Gottlieb E. Reversed argininosuccinate lyase activity in fumarate hydratase-deficient cancer cells. Cancer & Metabolism 1: 12, 2013

Gonzalvez F, D'Aurelio M, Boutant M, Moustapha A, Puech JP, Landes T, Arnauré L, Vial G, Talleux N, Slomianny C, Wanders RJ, Houtkooper RH, Belenger P, Møller IM, Gottlieb E, Vaz FM, Manfredi G, Petit PX. Barth syndrome: Cellular compensation of mitochondrial dysfunction and apoptosis inhibition due to changes in cardiolipin remodeling linked to tafazzin gene mutation. Biochim Biophys Acta. 1832: 1194-1206, 2013

Jalmar O, François-Moutal L, García-Sáez AJ, Perry M, Granjon T, Gonzalvez F, Gottlieb E, Ayala-Sanmartin J, Klösgen B, Schwille P, Petit PX. Caspase-8 binding to cardiolipin in giant unilamellar vesicles provides a functional docking platform for bid. PLoS One 8(2): e55250, 2013

Long JS, Crighton D, O’Prey J, MacKay G, Zheng L, Palmer TM, Gottlieb E, Kevin M. Ryan KM. Extracellular adenosine sensing - a metabolic cell death priming mechanism downstream of p53. Molecular Cell, 50: 394-406, 2013

Maddocks ODK, Berkers CR, Mason SM, Zheng L, Blyth K, Gottlieb E, Vousden KH. Serine starvation induces stress and p53 dependent metabolic remodeling in cancer cells. Nature 493: 542-6, 2013

Rosenfeldt MT, O'Prey J, Morton JP, Nixon C, Mackay G, Mrowinska A, Au A, Rai TS, Zheng L, Ridgway R, Adams PD, Anderson KI, Gottlieb E, Sansom OJ, Ryan KM. p53 status determines the role of autophagy in pancreatic tumour development. Nature 2013. Epub 2013/12/07.

Tannahill GM, Curtis AM, Adamik J, Palsson-McDermott EM, McGettrick AF, Goel G, Frezza C, Bernard NJ, Kelly B, Foley NH, Zheng L, Gardet A, Tong Z, Jany SS, Corr SC, Haneklaus M, Caffrey BE, Pierce K, Walmsley S, Beasley FC, Cummins E, Nizet V, Whyte M, Taylor CT, Lin H, Masters SL, Gottlieb E, Kelly VP, Clish C, Auron PE, Xavier RJ, O’Neill LAJ. Succinate is an inflammatory signal that induces IL-1β through HIF-1α. Nature 496: 238–42, 2013

Nizet V, Whyte M, Taylor CT, Lin H, Masters SL, Gottlieb E, Kelly VP, Clish C, Auron PE, Xavier RJ, O’Neill LAJ. Succinate is an inflammatory signal that induces IL-1β through HIF-1α. Nature 496: 238–42, 2013

2012

Duran RV, Mackenzie ED, Boulahbel H, Frezza C, Heiserich L, Tardito S, Bussolati O, Rocha S, Hall MN, Gottlieb E. HIF-independent role of prolyl hydroxylases in the cellular response to amino acids. Oncogene doi: 10.1038/onc.2012.465, published online 22 Oct 2012

Chaneton B, Hillmann P, Zheng L, Martin AC, Maddocks OD, Chokkathukalam A, Coyle JE, Jankevics A, Holding FP, Vousden KH, Frezza C, O’Reilly M, Gottlieb E. Serine is a natural ligand and allosteric activator of pyruvate kinase M2. Nature 491: 458-62, 2012

Duran RV, Oppliger W, Robitaille AM, Heiserich L, Skendaj R, Gottlieb E, Hall MN. Glutaminolysis Activates Rag-mTORC1 Signaling. Mol Cell 47: 349-58, 2012

Chaneton B, Gottlieb E. PGAMgnam style: A glycolytic switch controls biosynthesis. Cancer Cell 22: 565-6, 2012

Chaneton B, Gottlieb E. Rocking cell metabolism: revised functions of the key glycolytic regulator PKM2 in cancer. Trends Biochem Sci 37: 309-16, 2012

Schug ZT, Frezza C, Galbraith LC, Gottlieb E. The music of lipids: how lipid composition orchestrates cellular behaviour. Acta Oncol 51: 301-10, 2012

2011

Frezza C, Zheng L, Folger O, Rajagopalan KN, Mackenzie ED, Jerby L, Micaroni M, Chaneton B, Adam J, Hedley A, Kalna G, Tomlinson IP, Pollard PJ, Watson DG, Deberardinis RJ, Shlomi T, Ruppin E, Gottlieb E (2011). Haem oxygenase is synthetically lethal with the tumour suppressor fumarate hydratase. Nature 477(7363):225-8, 2011

Frezza C, Zheng L, Tennant DA, Papkovsky DB, Hedley BA, Kalna G, Watson DG, Gottlieb E. Metabolic profiling of hypoxic cells revealed a catabolic signature required for cell survival. PLoS One 2011; 6: e24411

Schug ZT, Gonzalvez F, Houtkooper RH, Vaz FM, Gottlieb E. BID is cleaved by caspase-8 within a native complex on the mitochondrial membrane. Cell Death Differ 2011; 18: 538–48

Gottlieb E (2011). p53 guards the metabolic pathway less travelled. Nat Cell Biol. 13, 195-7.

Frezza C, Pollard PJ, Gottlieb E (2011). Inborn and acquired metabolic defects in cancer. J Mol Med. 89, 213-20.

Folger O, Jerby L, Frezza C, Gottlieb E, Ruppin E, Shlomi T (2011). Predicting selective drug targets in cancer through metabolic networks. Mol Syst Biol. 7, 517.

Shlomi T, Benyamini T, Gottlieb E, Sharan R, Ruppin E (2011). Genome-scale metabolic modeling elucidates the role of proliferative adaptation in causing the Warburg effect. PLoS Comput Biol 7, e1002018.

Galluzzi L, Vitale I, Abrams JM, Alnemri ES, Baehrecke EH, Blagosklonny MV, Dawson TM, Dawson VL, El-Deiry WS, Fulda S, Gottlieb E, Green DR, Hengartner MO, Kepp O, Knight RA, Kumar S, Lipton SA, Lu X, Madeo F, Malorni W, Mehlen P, Nunez G, Peter ME, Piacentini M, Rubinsztein DC, Shi Y, Simon HU, Vandenabeele P, White E, Yuan J, Zhivotovsky B, Melino G, Kroemer G. Molecular definitions of cell death subroutines: recommendations of the Nomenclature Committee on Cell Death 2012. Cell Death Differ doi: 10.1038/cdd.2011.96, published online 15 Jul 2011

2010

Tennant DA, Gottlieb E (2010). HIF prolyl hydroxylase-3 mediates alpha-ketoglutarate-induced apoptosis and tumor suppression. J Mol Med. 88, 839-49.

Tennant DA, Duran RV, Gottlieb E (2010). Targeting metabolic transformation for cancer therapy. Nat Rev Cancer 10, 267-77.

Images

Gottlieb_1131369244.jpg

Studying mitochondrial structure using a scanning electron microscope. Mitochondria were purified by Francois Gonzalvez (a former student in the lab) and the image was taken by Prof Terry Allen from the CR-UK Paterson Institute in Manchester.

Lab Members

gottlieb lab 2013

Post-docs

Simone Cardaci (FEBS)
Johan Vande Voorde (CRUK Discovery Committee/AstraZeneca)

Scientific Officer

Elaine MacKenzie

Clinical Research Fellow

Henry Dabritz (NHS)

PhD Students

Elodie Kuntz
Jiska van der Reest

Former Lab Members

Saverio Tardito, Group Head, CRUK Beatson Institute, Glasgow
Zach Schug, Group Head, US
Christian Frezza, Group Head, Hutchinson, Cambridge
Lisa Heiserich, Research and Product Manager, Medipan, Germany
Dan Tennant, Lecturer, University of Birmingham, UK
Raul Duran, Postdoctoral Fellow, University of Basel, Switzerland; Group Leader, European Institute of Chemistry and Biology (IECB) Bordeaux, France
Francois Gonzalvez, Postdoctoral Fellow, Genetech Inc, South San Francisco, USA; ARIAD Pharmaceuticals, Cambridge MA, USA

Research

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Seminars

Beatson Institute Seminars

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

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