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MRC Cancer Unit


c frezza

Dr Christian Frezza

Biography | Pubmed

The metabolic determinants of cancerous transformation

Cancer cannot be defined as a single disease, but rather a collection of diseases with distinct histopathological and genetic features. Nevertheless, all cancers share many common traits, among which dysregulated metabolism is chief. It is now clear that several metabolic pathways converge to provide the cancer cell with all the nutrients required for unrestrained growth and proliferation. Yet, the extent at which dysregulated metabolism contributes to the cancerous transformation is poorly understood. Mutations in enzymes including the Tricarboxylic acid (TCA) cycle enzymes Succinate Dehydrogenase (SDH), Fumarate Hydratase (FH), and Isocitrate Dehydrogenase (IDH) have been shown to cause hereditary and sporadic forms of cancer. These recent discoveries provide evidence of an unanticipated cancer-causing role of mutated metabolic enzymes.

Our laboratory seeks to understand the contribution of dysregulated metabolism to tissue-specific carcinogenesis. A part of the lab is investigating how the loss of FH causes HLRCC. While rare, HLRCC provides a tractable paradigm where it is clear that a metabolic event initiates cancer. Furthermore, HLRCC individuals represent an unmet need in terms of cancer prevention and management. Another part of the lab is working on the metabolic determinants of cancer initiation and progression in renal cancer.

Our work has multiple implications: (1) it will provide a mechanistic understanding of the role of metabolism and small molecule metabolites in the early phases of cancer transformation and how metabolism contributes to tissue-specific tumorigenesis; (2) it will generate experimental and computation tools to identify metabolic vulnerabilities in cancer cells that we can use as pharmacological targets for cancer therapy; (3) it will apply metabolomics and multi-omics analyses, to mouse and human models to identify metabolic markers of disease initiation for clinical application in early detection and for patient stratification.


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Selected Publications:

Oncometabolites in renal cancer. Yong C, Stewart GD, Frezza C. Nat Rev Nephrol. 2019 Oct 21. doi: 10.1038/s41581-019-0210-z. [Epub ahead of print] Review. PMID: 31636445

Fumarate hydratase in cancer: A multifaceted tumour suppressor. Schmidt C, Sciacovelli M, Frezza C.Semin Cell Dev Biol. 2019 May 22. pii: S1084-9521(18)30202-7. doi: 10.1016/j.semcdb.2019.05.002. [Epub ahead of print] Review.PMID: 31085323

Fumarate hydratase loss promotes mitotic entry in the presence of DNA damage after ionising radiation. Johnson TI, Costa ASH, Ferguson AN, Frezza C. Cell Death Dis. 2018 Sep 6;9(9):913. doi: 10.1038/s41419-018-0912-3.

NADH shuttling couples cytosolic reductive carboxylation of glutamine with glycolysis in cells with mitochondrial dysfunction.Gaude E, Schmidt C, Gammage PA, Dugourd A, Blacker T, Chew SP , Saez-Rodriguez J, O’Neill SJ, Szabadkai G, Minczuk M and Frezza C. Mol Cell, 2018 Feb. 10.1016/j.molcel.2018.01.034

Post-translational regulation of metabolism in fumarate hydratase deficient cancer cells. Gonçalves E, Sciacovelli M, Costa ASH, Tran MGB, Johnson TI, Machado D, Frezza C*, Saez-Rodriguez J*. Metab Eng. 2017 Nov 27. doi: 10.1016/j.ymben.2017.11.011. *: co-corresponding authors

Fumarate Hydratase Loss Causes Combined Respiratory Chain Defects.Tyrakis PA, Yurkovich EM, Sciacovelli M, Papachristou EK, Bridges HR, Gaude E, Schreiner A, D’Santos C, Hirst J, Hernandez-Fernaud J, Springett R, Griffiths JR, Frezza C. Cell Reports. 2017 Oct 24. doi: 10.1016/j.celrep.2017.09.092.

Mitochondrial Metabolism: Yin and Yang for Tumor Progression. Valcarcel-Jimenez L, Gaude E, Torrano V, Frezza C, Carracedo A. Trends Endocrinol Metab. 2017 Jul 18. pii: S1043-2760(17)30087-5. doi: 10.1016/j.tem.2017.06.004.


Metabolic synthetic lethality in cancer therapy. Zecchini V1, Frezza C2. Biochim Biophys Acta. 2016 Dec 9. pii: S0005-2728(16)30679-X. doi: 10.1016/j.bbabio.2016.12.003

Tissue-specific and convergent metabolic transformation of cancer correlates with metastatic potential and patient survival. Gaude E1, Frezza C1. Nat Commun. 2016 Oct 10;7:13041. doi: 10.1038/ncomms13041.

Fumarate is an epigenetic modifier that elicits epithelial-to-mesenchymal transition. Sciacovelli M, Gonçalves E, Johnson TA, Zecchini V,
Costa SA, Gaude E, Drubbel A, Theobald S, Abbo S, Tran M, 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. Nature. 2016 Aug 31.

Near-complete elimination of mutant mtDNA by iterative or dynamic dose-controlled treatment with mtZFNs. Gammage PA, Gaude E, Van Haute L, Rebelo-Guiomar P, Jackson CB, Rorbach J, Pekalski ML, Robinson AJ, Charpentier M, Concordet JP, Frezza C, Minczuk M. Nucleic Acids Res. 2016 Jul 27.

Distinct Metabolic Requirements of Exhausted and Functional Virus-Specific CD8 T Cells in the Same Host. Schurich A, Pallett LJ, Jajbhay D, Wijngaarden J, Otano I, Gill US, Hansi N, Kennedy PT, Nastouli E, Gilson R, Frezza C, Henson SM, Maini MK. Cell Rep. 2016 Jul 20.

Cancer metabolism: Addicted to serine. Frezza C. Nat Chem Biol. 2016 May 18;12(6):389-90.

Oncometabolites: Unconventional triggers of oncogenic signalling cascades. Sciacovelli M, Frezza C. Free Radic Biol Med. 2016 Apr 23.

Mutant Kras copy number defines metabolic reprogramming and therapeutic susceptibilities. Kerr EM, Gaude E, Turrell FK, Frezza C, Martins CP. Nature. 2016 Mar 3;531(7592):110-3.

Succinate metabolism: a new therapeutic target for myocardial reperfusion injury. Pell VR, Chouchani ET, Frezza C, Murphy MP, Krieg T. Cardiovasc Res. 2016 May 18. [Epub ahead of print] Review.

Cancer metabolism: Addicted to serine. Frezza C. Nat Chem Biol. 2016 May 18;12(6):389-390. doi: 10.1038/nchembio.2086.

Oncometabolites: Unconventional triggers of oncogenic signalling cascades. Sciacovelli M, Frezza C. Free Radic Biol Med. 2016 Apr 23. [Epub ahead of print]

Hypoxia-induced nitric oxide production and tumour perfusion is inhibited by pegylated arginine deiminase (ADI-PEG20). Burrows N, Cane G, Robson M, Gaude E, J Howat W, Szlosarek PW, Pedley RB, Frezza C, Ashcroft M, Maxwell PH. Sci Rep. 2016 Mar 14;6:22950.

Mutant Kras copy number defines metabolic reprogramming and therapeutic susceptibilities. Kerr EM, Gaude E, Turrell FK, Frezza C, Martins CP. Nature. 2016 Mar 3;531(7592):110-3. Epub 2016 Feb 24.

Accumulated metabolites of hydroxybutyric acid serve as diagnostic and prognostic biomarkers of high-grade serous ovarian carcinomas. Hilvo M, de Santiago I, Gopalacharyulu P, Schmitt WD, Budczies J, Kuhberg M, Dietel M, Aittokallio T, Markowetz F, Denkert C, Sehouli J, Frezza C, Darb-Esfahani S, Braicu EI. Cancer Res. 2015 Dec 18. pii: canres.2298.2015. [Epub ahead of print]

A three-dimensional engineered tumour for spatial snapshot analysis of cell metabolism and phenotype in hypoxic gradients. Rodenhizer D, Guade E, Cojocari D, Mahadevan R, Frezza C, Wouters BG, McGuigan AP. Nat Mater. 2015 Nov 23. doi: 10.1038/nmat4482. [Epub ahead of print]

Designing a broad-spectrum integrative approach for cancer prevention and treatment. BlockKI, Charlotte GyllenhaalC, Lowe L, AmedeiA, AminR, Amin A, and 174 other members of the Halifax Project Research Team. Semin Cancer Biol. 2015 Dec;35 Suppl:S276-304.doi: 10.1016/j.semcancer.2015.09.007. Review.

Dysregulated metabolism contributes to oncogenesis. Hirschey MD, DeBerardinis RJ, Diehl AM, Drew JE, Frezza C, Green MF, Jones LW, Ko YH, Le A, Lea MA, Locasale JW, Longo VD, Lyssiotis CA, McDonnell E, Mehrmohamadi M, Michelotti G, Muralidhar V, Murphy MP, Pedersen PL, Poore B, Raffaghello L, Rathmell JC, Sivanand S, Heiden MG, Wellen KE; Target Validation Team. Semin Cancer Biol. 2015 Oct 8. pii: S1044-579X(15)00099-1. doi:10.1016/j.semcancer.2015.10.002. [Epub ahead of print] Review.

Cell surface proteomic map of HIV infection reveals antagonism of amino acid metabolism by Vpu and Nef. Matheson NJ, Sumner J, Wals K, Rapiteanu R, Weekes MP, Vigan R, Weinelt J, Schindler M, Antrobus R, Costa AS, Frezza C, Clish CB, Neil SJ, Lehner PJ. Cell Host Microbe. 2015 Sep 29 pii: S1931-3128(15)00372-8. doi: 10.1016/j.chom.2015.09.003. [Epub ahead of print].

Inhibition of glucose-6-phosphate dehydrogenase sensitizes cisplatin-resistant cells to death. Catanzaro D, Gaude E, Orso G, Giordano C, Guzzo G, Rasola A, Ragazzi E, Caparrotta L, Frezza C, Montopoli M. Oncotarget. 2015 Aug 17 [Epub ahead of print].

Metabolic reprograming of mononuclear phagocytes in progressive multiple sclerosis. Tannahill GM, Iraci N, Gaude E, Frezza C, Pluchino S. Front Immunol. 2015 Mar 11;6:106. doi: 10.3389/fimmu.2015.00106. eCollection 2015. Review. Free PMC Article.

A roadmap for interpreting 13C metabolite labeling patterns from cells. 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, Nöh 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. Curr Opin Biotechnol. 2015 Feb 28;34:189-201. doi: 10.1016/j.copbio.2015.02.003. [Epub ahead of print] Review.

Fumarate induces redox-dependent senescence by modifying glutathione metabolism. 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. at Commun. 2015 Jan 23;6:6001. doi: 10.1038/ncomms7001.

Editorial: The Metabolic Challenges of Immune Cells in Health and Disease. Frezza C, Mauro C. Front Immunol. 2015 Jun 4;6:293. doi:10.3389/fimmu.2015.00293. eCollection 2015. No abstract available.

Proteomics-based metabolic modelling reveals that fatty acid oxidation controls endothelial cell permeability. 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. Mol Cell Proteomics. 2015 Jan 8. pii: mcp.M114.045575. [Epub ahead of print]

Phenotype-based cell-specific metabolic modeling reveals metabolic liabilities of cancer. Yishak K, Gaude E, Le Dévédec S, Waldman YY, Stein GY, van de Water B, Frezza C, Ruppin E. Elife. 2014 Nov 21;3. doi: 10.7554/eLife.03641.

Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS. Chouchani ET, Pell VR, Gaude E, Aksentijević D, Sundier SY, Robb EL, Logan A, Nadtochiy SM, Ord EN, Smith AC, Eyassu F, Shirley R, Hu CH, Dare AJ, James AM, Rogatti S, Hartley RC, Eaton S, Costa AS, Brookes PS, Davidson SM, Duchen MR, Saeb-Parsy K, Shattock MJ, Robinson AJ, Work LM, Frezza C, Krieg T, Murphy MP. Nature. 2014 Nov 20;515(7527):431-5. doi: 10.1038/nature13909. Epub 2014 Nov 5.

A computational study of the Warburg effect identifies metabolic targets inhibiting cancer migration. Yizhak K, Le Dévédec SE, Rogkoti VM, Baenke F, de Boer VC, Frezza C, Schulze A, van de Water B, Ruppin E. Mol Syst Biol. 2014 Aug 1;10(8):744. doi: 10.15252/msb.20134993.

Defects in mitochondrial metabolism and cancer. Gaude E, Frezza C. Cancer Metab. 2014 Jul 17;2:10. doi: 10.1186/2049-3002-2-10. eCollection 2014. Review.

Germline FH mutations presenting with pheochromocytoma. Clark GR, Sciacovelli M, Gaude E, Walsh DM, Kirby G, Simpson MA, Trembath RC, Berg JN, Woodward ER, Kinning E, Morrison PJ, Frezza C, Maher ER. J Clin Endocrinol Metab. 2014 Jul 8:jc20141659.

The metabolic alterations of cancer cells. Sciacovelli M, Gaude E, Hilvo M, Frezza C. Methods Enzymol. 2014;542:1-23. doi: 10.1016/B978-0-12-416618-9.00001-7.

Nuclear ARRB1 induces pseudohypoxia and cellular metabolism reprogramming in prostate cancer. Zecchini V, Madhu B, Russell R, Pértega-Gomes N, Warren A, Gaude E, Borlido J, Stark R, Ireland-Zecchini H, Rao R, Scott H, Boren J, Massie C, Asim M, Brindle K, Griffiths J, Frezza C, Neal DE, Mills IG. EMBO J. 2014 Jun 17;33(12):1365-82. doi: 10.15252/embj.201386874.

High throughput synthetic lethality screen reveals a tumorigenic role of adenylate cyclase in fumarate hydratase-deficient cancer cells. Boettcher M, Lawson A, Ladenburger V, Fredebohm J, Wolf J, Hoheisel JD, Frezza C, Shlomi T. BMC Genomics. 2014 Feb 25;15:158. doi: 10.1186/1471-2164-15-158.

The role of mitochondria in the oncogenic signal transduction. Frezza C. Int J Biochem Cell Biol. 2014 Mar;48:11-7. doi: 10.1016/j.biocel.2013.12.013.

Reversed argininosuccinate lyase activity in fumarate hydratase-deficient cancer cells. Zheng L, Mackenzie ED, Karim SA, Hedley A, Blyth K, Kalna G, Watson DG, Szlosarek P, Frezza C, Gottlieb E. Cancer Metab. 2013 Mar 21;1(1):12. doi: 10.1186/2049-3002-1-12.

The mitochondrial chaperone TRAP1 promotes neoplastic growth by inhibiting succinate dehydrogenase. Sciacovelli M, Guzzo G, Morello V, Frezza C, Zheng L, Nannini N, Calabrese F, Laudiero G, Esposito F, Landriscina M, Defilippi P, Bernardi P, Rasola A. Cell Metab. 2013 Jun 4;17(6):988-99. doi: 10.1016/j.cmet.2013.04.019.

Serine is a natural ligand and allosteric activator of pyruvate kinase M2. 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. Nature. 2012 Nov 15;491(7424):458-62. doi: 10.1038/nature11540.

Haem oxygenase is synthetically lethal with the tumour suppressor fumarate hydratase. 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. Nature. 2011 Aug 17;477(7363):225-8.

Metabolic profiling of hypoxic cells revealed a catabolic signature required for cell survival. Frezza C, Zheng L, Tennant DA, Papkovsky DB, Hedley BA, Kalna G, Watson DG, Gottlieb E. PLoS One. 2011;6(9):e24411.