1. Research Background:
Our laboratory seeks to understand the contribution of dysregulated metabolism to age-associated disorders, focusing on cancer as a disease model. In particular, we are investigating how the loss of the mitochondrial enzyme and tumour suppressor Fumarate Hydratase (FH) causes Hereditary Leiomyomatosis and Renal Cell Carcinoma (HLRCC).
FH catalyses the reversible hydration of fumarate to malate within the TCA, a key metabolic pathway for the cell. Our work showed that upon FH loss, renal cells engage in a complex metabolic reprogramming that is required for cell survival and growth. Importantly, a defining biochemical feature of FH loss is the accumulation of fumarate, which has been implicated in tumorigenesis, acting as an oncometabolite. For instance, accumulated fumarate can bind and inactivate reactive thiol residues of proteins and peptides in a process called succination. Succination of key reactive thiol residues of Keap1, the negative regulator of the antioxidant master gene NRF2, leads to a powerful antioxidant response. Additionally, fumarate inhibits several alpha-ketoglutarate (αKG)-dependent dioxygenases (αKGDDs), a family of enzymes involved in diverse cellular processes from metabolism to signalling and the de-methylation of DNA, RNA, and histones. Indeed, fumarate has been shown to act as a potent inhibitor of the DNA demethylases Ten Eleven Translocation (TET) enzymes and a series of histone demethylases. Our group showed that fumarate accumulation drives an epithelial-to-mesenchymal transition (EMT) via the epigenetic suppression of a family of antimetastatic miRNA. Yet, how metabolic reprogramming and the multi-layer signalling triggered by fumarate contribute to tissue specific tumorigenesis is only partially know.
2. Research questions addresses by the group:
In our laboratory we seek to understand how the signals elicited by fumarate trigger transformation in a time- and tissue-specific manner. In particular, we investigate the determinant of tissue specific transformation, looking at how the loss of FH loss is tolerated in the different tissues. We hypothesise that only in tissue with sufficient metabolic flexibility the loss of FH can be buffered, thus avoiding cell death. Here, the accumulation of fumarate could then activate specific oncogenic signalling cascades. Another research question that we want to address is how, once cells adapt to the loss of FH, fumarate elicits transformation. We study the roles of fumarate as an epigenetic modifier and as an electrophile capable of inducing protein succination. Finally, we want to further study the molecular connection between FH loss and inflammation that we have recently discovered.
3. Possible projects:
Projects will be discussed with the candidates and will depend on their interests and skills but will focus on the following aspects of FH biology:
- Investigation of the tissue-specific metabolic adaptations to FH loss using in vivo models of FH deficiency
- The evolution of FH-deficient clones in the kidney
- Investigation of the role of protein succination in FH biology
- The role of inflammation in HLRCC
- Mechanisms that lead to fumarate accumulation in non-FH-deficient cells
4. Applied Methods and model organisms:
All projects will be highly multidisciplinary and will combine the integration of multiomics datasets (metabolomics, proteomics, and epigenomics) using computational approaches applied to cell lines and mouse models. In particular, you will have access to state-of-the-art metabolomics platforms and unique models to investigate FH biology.
5. Desirable skills and qualifications:
Knowledge in biochemistry, cell culture, and computational studies. A passion for metabolism and mitochondrial biology is a bonus. Experience with mouse work is important for specific parts of the above-indicated projects.
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- Gaude E, Schmidt C, Gammage PA, Dugourd A, Blacker T, Chew SP, Saez- Rodriguez J, O'Neill JS, Szabadkai G, Minczuk M, Frezza C. NADH Shuttling Couples Cytosolic Reductive Carboxylation of Glutamine with Glycolysis in Cells with Mitochondrial Dysfunction. Mol Cell. 2018 Feb 15;69(4):581-593.e7. doi: 10.1016/j.molcel.2018.01.034. PMID: 29452638; PMCID: PMC5823973.
- Gonçalves E, Sciacovelli M, Costa ASH, Tran MGB, Johnson TI, Machado D, Frezza C*, Saez-Rodriguez J*. Post-translational regulation of metabolism in fumarate hydratase deficient cancer cells. Metab Eng. 2018 Jan;45:149-157. doi: 10.1016/j.ymben.2017.11.011. Epub 2017 Nov 27. PMID: 29191787; PMCID: PMC5805855. *: co-last authors
- Tyrakis PA, Yurkovich ME, Sciacovelli M, Papachristou EK, Bridges HR, Gaude E, Schreiner A, D'Santos C, Hirst J, Hernandez-Fernaud J, Springett R, Griffiths JR, Frezza C. Fumarate Hydratase Loss Causes Combined Respiratory Chain Defects. Cell Rep. 2017 Oct 24;21(4):1036-1047. doi: 10.1016/j.celrep.2017.09.092. PMID: 29069586; PMCID: PMC5668630.
- Gaude E, Frezza C. Tissue-specific and convergent metabolic transformation of cancer correlates with metastatic potential and patient survival. Nat Commun. 2016 Oct 10;7:13041. doi: 10.1038/ncomms13041. PMID: 27721378; PMCID: PMC5062467.
- 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;537(7621):544-547. doi: 10.1038/nature19353. Erratum in: Nature. 2016 Dec 1;540(7631):150. PMID: 27580029; PMCID: PMC5136292.
- 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. 2015 Jan 23;6:6001. doi: 10.1038/ncomms7001. PMID: 25613188; PMCID: PMC4340546.*:co-corresponding authors
- Boettcher M, Lawson A, Ladenburger V, Fredebohm J, Wolf J, Hoheisel JD, Frezza C*, Shlomi T*. High throughput synthetic lethality screen reveals a tumorigenic role of adenylate cyclase in fumarate hydratase-deficient cancer cells. BMC Genomics. 2014 Feb 25;15:158. doi: 10.1186/1471-2164-15-158. PMID: 24568598; PMCID: PMC3945041. *: co-corresponding authors
- 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 Metab. 2013 Mar 21;1(1):12. doi: 10.1186/2049-3002-1-12. PMID: 24280230; PMCID: PMC4108060. *: co-corresponding authors
- 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(9):e24411. doi: 10.1371/journal.pone.0024411. Epub 2011 Sep 2. PMID: 21912692; PMCID: PMC3166325.
- 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. Haem oxygenase is synthetically lethal with the tumour suppressor fumarate hydratase. Nature. 2011 Aug 17;477(7363):225-8. doi: 10.1038/nature10363. PMID: 21849978.