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

2017

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 Rep 2017; 18: 647-58

Fack F, Tardito S, Hochart G, Oudin A, Zheng L, Fritah S, Golebiewska A, Nazarov PV, Bernard A, Hau AC, Keunen O, Leenders W, Lund-Johansen M, Stauber J, Gottlieb E, Bjerkvig R, Niclou SP. Altered metabolic landscape in IDH-mutant gliomas affects phospholipid, energy, and oxidative stress pathways. EMBO Mol Med 2017; 9: 1681-95

Kuntz EM, Baquero P, Michie AM, Dunn K, Tardito S, Holyoake TL, Helgason GV, Gottlieb E. Targeting mitochondrial oxidative phosphorylation eradicates therapy-resistant chronic myeloid leukemia stem cells. Nat Med 2017 23: 1234-40

Monterisi S, Lobo MJ, Livie C, Castle JC, Weinberger M, Baillie GS, Surdo NC, Musheshe N, Stangherlin A, Gottlieb E, Maizels RJ, Bortolozzi M, Micaroni M, Zaccolo M. PDE2A2 regulates mitochondria morphology and apoptotic cell death via local modulation of cAMP/PKA signalling. Elife 2017; 6: pii: e21374

Gottlieb E, Vousden KH. One carbon, many roads. Cell Death Differ 2017 24: 193-4

2016

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 10: 73-84, 2016

Farris JC, Pifer PM, Zheng L, Gottlieb E, Denvir J, Frisch SM. Grainyhead-like 2 reverses the metabolic changes induced by the oncogenic epithelial-mesenchymal transition: Effects on anoikis. Mol Cancer Res 14: 528-38, 2016

Karvela M, Baquero P, Kuntz EM, Mukhopadhyay A, Mitchell R, Allan EK, Chan E, Kranc KR, Calabretta B, Salomoni P, Gottlieb E, Holyoake TL, Helgason GV. ATG7 regulates energy metabolism, differentiation and survival of Philadelphia-chromosome-positive cells. Autophagy 12: 936-48, 2016

Lu YW, Galbraith L, Herndon JD, Lu YL, Pras-Raves M, Vervaart M, Van Kampen A, Luyf A, Koehler CM, McCaffery JM, Gottlieb E, Vaz FM, Claypool SM. Defining functional classes of Barth syndrome mutation in humans. Hum Mol Genet 25: 1754-70, 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

Mills EL, Kelly B, Logan A, Costa ASH, Varma M, Bryant CE, Tourlomousis P, Dabritz JHM, Gottlieb E, Latorre I, Corr SC, McManus G, Ryan D, Jacobs HT, Szibor M, Xavier RJ, Braun T, Frezza C, Murphy MP, O'Neill LA. Succinate dehydrogenase supports metabolic repurposing of mitochondria to drive inflammatory macrophages. Cell 167: 457-70, 2016

Peck B, Schug ZT, Zhang Q, Dankworth B, Jones DT, Smethurst E, Patel R, Mason S, Jiang M, Saunders R, Howell M, Mitter R, Spencer-Dene B, Stamp G, McGarry L, James D, Shanks E, Aboagye EO, Critchlow SE, Leung HY, Harris AL, Wakelam MJ, Gottlieb E, Schulze A. Inhibition of fatty acid desaturation is detrimental to cancer cell survival in metabolically compromised environments. Cancer Metab 4: 6, 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 537: 544-7, 2016

Trousil S, Kaliszczak M, Schug Z, Nguyen QD, Tomasi G, Favicchio R, Brickute D, Fortt R, Twyman FJ, Carroll L, Kalusa A, Navaratnam N, Adejumo T, Carling D, Gottlieb E, Aboagye EO. The novel choline kinase inhibitor ICL-CCIC-0019 reprograms cellular metabolism and inhibits cancer cell growth. Oncotarget 7: 37103-20, 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

Schug ZT, Vande Voorde J, Gottlieb E. The metabolic fate of acetate in cancer. Nat Rev Cancer 16: 708-17, 2016

Schug ZT, Voorde JV, Gottlieb E. The nurture of tumors can drive their metabolic phenotype. Cell Metab 23: 391-2, 2016

van der Reest J, Gottlieb E. Anti-cancer effects of vitamin C revisited. Cell Res 26: 269-70, 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

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

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 group

Post-docs

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

Scientific Officer

Elaine MacKenzie

Clinical Research Fellow

Henry Dabritz (NHS)

PhD Students

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
Elodie Kuntz
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

lab image 2017 2

Read more about the Research Groups working at the Beatson Institute.

More

Seminars

lab image 2017

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

More