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Christian Frezza

c frezza

Dr Christian Frezza

Biography | Pubmed

 

Understanding the Metabolic Transformation of Cancer Cells

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 unrestrained cellular proliferation is the most apparent.

The cellular signals that drive chronic proliferation have been extensively studied in the past decades, revealing a set of deregulated oncogenes and tumour suppressors. However, in order to sustain cell growth and proliferation cancer cells must undergo a complex metabolic transformation, whereby several metabolic pathways converge to provide the growing cell with all the nutrients required for this process (Figure 1). It is now emerging that several oncogenes and tumour suppressors, besides their role in cell signalling, control the activity of different metabolic pathways to support the metabolic transformation of a cancer cell.

Figure 1: The metabolic tranformation of a cancer cell. 

 

frezzafig1a
Schematic representation of the three major components of the metabolic rewiring observed in cancer cells. Mitochondrial metabolism, aerobic glycolysis, and fatty acid metabolism are deeply intertwined and cooperate to fulfil the increased biosynthetic demands of cancer cells. Full circles over the enzymatic reactions indicate that the reaction is controlled by oncogenes or tumour suppressor. The figure is adapted from Sciacovelli et al, Methods in Enzymology, 2013, where you can also find more details about the individual reactions.

 

The connection between cancer and metabolism has become even stronger after the discovery that some key mitochondrial enzymes such as Succinate Dehydrogenase, Fumarate Hydratase, and Isocitrate Dehydrogenase, if mutated, could lead to different forms of cancer. We now know that mitochondria are key organelles for cancer cells and mutations of Krebs cycle enzymes, or components of oxidative phosphorylation, predisposes to various types of cancer (Figure 2).  These findings suggest that altered metabolism is not only a required event to support proliferation but in some instances can be the leading cause of cancer, tracing back to the initial hypothesis of Otto Warburg, a pioneer in the field of cancer metabolism. 

By using a combination of biochemistry, metabolomics, and systems biology our team is investigating the role of altered metabolism in cancer and striving to address the following key questions:

1. How does mitochondrial dysfunction deregulate cell metabolism and predisposes to tumorigenesis?

2. How is the process of cancer evolution shaped by the altered cancer metabolism?

3. How does cancer metabolism alter the tumour microenvironment?

 

 Figure 2: Mitochondrial enzyme defects are linked to cancer.

 

frezzafig2b
Mutations of Krebs cycle enzymes (A) and of components of oxidative phosphorylation (B) are associated to human cancers. The figure has been adapted from Gaude and Frezza, Cancer and Metabolism, 2014.


For more information on cancer metabolism and interesting developments in the field visit the Cancer Metabolism Facebook page.

 

Contact:

Click to contact Dr Christian Frezza by email.

 

Selected Publications:

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 oncogenesisHirschey 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.