Group Leader: Dr Christian Frezza
Dr Marco Sciacovelli, Post-Doctoral Researcher
I gained my MSc in Pharmacy at the University of Padova (Italy) back in 2007, after a period of ten months of research in Prof Di Lisa’s laboratory. During that period, I was involved in testing photoproducts of psoralen in the treatment of T-Cells Lymphomas. I investigated the mitochondrial toxicity of these compounds and apoptosis induction in Jurkat cells.
In 2007 I joined the laboratory of Prof Bernardi at the University of Padova, where I started my PhD in Bioscience and Cellular Biology. In that period, I learnt the basis of mitochondrial physiology and pathology in cancer. My main project was focused on understanding the role of the mitochondrial chaperone TRAP1, and its involvement in both tumorigenesis and regulation of mitochondrial function.
I joined Christian Frezza’s lab in 2012 as an MRC Career Development Fellow and I’m currently a Research Associate. Here, I am trying to elucidate the role of metabolic alterations in tumorigenesis. In particular, I study the mechanisms that lead to mitochondrial dysfunction in fumarate hydratase (FH) deficient cells and the role of this enzyme in cancer development. More in details, I’m interested in the crosstalk between mitochondria and the nucleus and in the role of small molecules metabolites in epigenetic regulation of gene expression.
In 2015 I also joined Corpus Christi College in Cambridge as Research Associate.
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.
Sciacovelli M, Frezza C. Oncometabolites: Unconventional triggers of oncogenic signalling cascades. Free Radic Biol Med. 2016 Apr 23. pii: S0891-5849(16)30043-0. doi: 10.1016/j.freeradbiomed.2016.04.025. [Epub ahead of print]
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.
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. Germline FH mutations presenting with pheochromocytoma. J Clin Endocrinol Metab. 2014 Jul 8:jc20141659.
Sciacovelli M*, Gaude E*, Hilvo M*, Frezza C. The metabolic alterations of cancer cells. Methods Enzymol.2014; 542:1-23. *: shared contribution
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. The mitochondrial chaperone TRAP1 promotes neoplastic growth by inhibiting succinate dehydrogenase. Cell Metab. 2013 Jun 4; 17(6):988-99.
Rasola A, Sciacovelli M, Chiara F, Pantic B, Brusilow WS, Bernardi P. Activation of mitochondrial ERK protects cancer cells from death through inhibition of the permeability transition. Proc Natl Acad Sci USA. 2010 Jan 12; 107(2):726-31.
Dr Vincent Zecchini, Post-Doctoral Researcher
I obtained my degree in Biochemistry from Liège, Belgium in 1992. After a short spell doing my military service in Germany, I obtained three years of funding to work on a joint academic-industry research project at Eurogentec, Liège, Belgium. My research led to the development and optimisation of a non-radioactive nucleic acid probe for the detection of Clostridium tyrobutyricum, a bacterium that causes “late blowing” of cheese manufactured with contaminated milk.
Following this, I moved to Cambridge to join the Developmental Biology laboratory of Professor Martinez-Arias at the Departments of Zoology and Genetics, where I started my PhD on a Wellcome Trust grant. I enjoyed four exciting years of research on Notch signalling investigating “A novel activity of Notch regulates JNK activity and apoptosis in Drosophila”.
Having not had enough of Notch by then, I was happy to be offered a post-doc position in the lab of Dr Phil Jones in the MRC Cancer Unit at the Hutchison/MRC Research Centre in Cambridge. In collaboration with Dr Doug Winton’s lab, we built an inducible knock-in transgenic mouse to investigate the role of Notch on the fate of mouse intestinal stem cells and its implications in cancer development.
A short two year digression in the laboratory of Professor David Rubinsztein at the Cambridge Institute for Medical Research, working on the role of LRRK2 in the etiology of Parkinson's disease, saw me returning to my roots in the form of a post-doc in the laboratory of Professor David Neal in the Oncology Department at the (then) CRUK Cambridge Research Institute. There, inspired by the enthusiasm of Dr Ian Mills, I worked on several projects including the molecular mechanisms underlying castrate-resistant prostate cancer and the role of endocytic adaptor ARRB1 in the modulation of cellular metabolism in prostate cancer. During this period I developed a keen interest in the field of cancer metabolism that resulted in me looping the loop to re-join the Hutchison/MRC building in April 2014, as a post-doc in the laboratory of Dr Christian Frezza.
My research interests are the role of metabolic alterations in tumorigenesis. My current project focuses on metabolic permissiveness and chemoprevention in tumorigenesis as a consequence of mitochondrial dysfunction using a Fumarate Hydratase (FH) deficiency mouse model. I am also in the preliminary steps of developing a project on the role of lysosome dysfunction and mTOR signalling in renal 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. Nuclear ARRB1 induces pseudohypoxia and cellular metabolism reprogramming in prostate cancer. EMBO J. 2014 Jun 17;33(12):1365-82
Sharma NL, Massie CE, Ramos-Montoya A, Zecchini V, Scott HE, Lamb AD, MacArthur S, Stark R, Warren AY, Mills IG, Neal DE. The androgen receptor induces a distinct transcriptional program in castration-resistant prostate cancer in man. Cancer Cell. 2013 Jan 14;23(1):35-47.
Zecchini V, Neal DE. Targeting the pro-survival side-effects of androgen-deprivation therapy in prostate cancer. BJU Int. 2013 Apr;111(4):532-3.
Massie CE, Lynch A, Ramos-Montoya A, Boren J, Stark R, Fazli L, Warren A, Scott H, Madhu B, Sharma N, Bon H, Zecchini V, Smith DM, Denicola GM, Mathews N, Osborne M, Hadfield J, Macarthur S, Adryan B, Lyons SK, Brindle KM, Griffiths J, Gleave ME, Rennie PS, Neal DE, Mills IG. The androgen receptor fuels prostate cancer by regulating central metabolism and biosynthesis. EMBO J. 2011 May 20;30(13):2719-33.
Lichtenberg M, Mansilla A, Zecchini VR, Fleming A, Rubinsztein DC. The Parkinson's disease protein LRRK2 impairs proteasome substrate clearance without affecting proteasome catalytic activity. Cell Death Dis. 2011 Aug 25;2:e196.
Dr Sofia Costa, Mass Spectrometry Specialist
I studied Animal Science at the University of Trás-os-Montes e Alto Douro (UTAD, Vila Real, Portugal). I then moved to Lisbon to do a Masters in Animal Production at the Faculty of Veterinary Medicine (Technical University of Lisbon, Portugal), having focused my work on angiogenesis and apoptosis in the equine corpus luteum.
In late 2008 I became research assistant at the Biochemistry Lab of the Faculty of Veterinary Medicine (Technical University of Lisbon, Portugal), studying lipid metabolism and its genetic regulation in ruminants. In 2013 I completed my PhD in Veterinary Sciences (Faculty of Veterinary Medicine, University of Lisbon, Portugal), during which I studied the genetic and metabolic regulation of fatty acid deposition in autochthonous bovine breeds from distinct genetic backgrounds. I then obtained an Albert Renold Travel Fellowship for Young Scientists from the European Foundation for the study of diabetes, which allowed me to spend 6 months working as a visiting researcher in the Regulation of Lipid Metabolism Group (School of Pharmacy, University of Barcelona, Spain). Here, I acquired new skills on adipocyte cell culture, and broadened my knowledge on the regulation of lipid metabolism in the context of diabetes. I also established the foundations for the study of the cross-talk between mammary tumour cells and adipocytes.
Currently, I’m a Research Associate managing the metabolomics facility in Christian Frezza’s laboratory. My work consists of advising on experimental design, identification and quantification of small molecule metabolites present in different matrices (biofluids, tissue, cell extracts, and others) by liquid chromatography coupled to mass spectrometry, as well as to perform data processing, statistical analysis, and interpretation of results. In collaboration with my colleagues and external researchers, and by combining analytical chemistry, biostatistics, and biochemistry to extract and integrate the biologically meaningful data, my work has contributed to further establish links between metabolic deregulation and oncogenesis (1), elucidate mechanisms of ischaemia-reperfusion injury (2), show viral interference with amino acid immunometabolism (3), and to identify a new DNA modification in higher eucaryotes (4).
Full list of publications: http://www.researcherid.com/rid/H-2852-2012
Isaac Johnson, PhD Student
In 2011, I graduated from the University of East Anglia in Norwich with a BSc in Biomedicine, with the idea of finding a position within a cancer research laboratory. During my final year I secured a summer internship working for four months at the Hutchison/MRC Research Centre in Prof Ashok Venkitaraman’s group where I successfully applied for a Research Assistant position that became available in the same group. I then worked for 1.5 years on multiple projects, gained vital experience and learnt invaluable techniques. It was from this period that I became interested in the critical processes by which cells maintain genomic integrity and the cellular routes to tumorigenesis.
However, the main insight my work as a Research Assistant gave me was the knowledge that I wanted to further develop my career through the self-directed study of a PhD.
When Dr Christian Frezza joined the building as a group leader in 2012, a PhD position opened in his lab and I was very fortunate to be given the MRC studentship for his group. Since starting in the lab in May 2013 and starting the PhD programme in October in the same year, I have begun to develop my project both conceptually and experimentally. One of the main things that drew me to Christian’s lab was the work on mitochondrial dysfunction and potential impact on cellular processes. One view of cells and metabolism can be considered “nucleo-centric”, that is genes encoded by nuclear DNA altering cellular metabolism. However, we considered the fact that the mitochondria, and mitochondria-related processes, directly feed into cellular and nuclear pathways where processes controlled by the mitochondria can alter these cellular responses. Given that genome maintenance is a critical cellular and metabolic process, we decided to interrogate the mechanisms that connect mitochondrial function, genome maintenance and cancer development. To address these questions, I am looking at how mitochondrial dysfunction caused by the loss of a mitochondrial tumour suppressor gene Fumarate Hydratase (FH) impinges on genome maintenance and how this could contribute to tumorigenesis.
Edoardo Gaude, PhD Student
I started my studies in Pharmaceutical Biotechnology with a BSc at the Universitá Vita-Salute San Raffaele, Milan, Italy, where I graduated in 2009 with full marks. I continued my studies with a MSc in Medical and Molecular Biotechnology at the same university, obtaining the final summa cum laude degree in 2012. During my Masters I worked for 18 months in the Biomolecular NMR lab investigating the extracellular and intracellular metabolic signature of neural stem/progenitor cells. Tackling the statistical analysis of “-omics” data I developed an R package called ‘muma’, which has been now published and freely accessible. After my Masters degree I kept working at the Biomolecular NMR Lab in Milan for 6 months as an “Anna Laura Segre” Fellow, performing different metabolomics analyses.
In 2012 I joined the laboratory of Christian Frezza at the MRC Cancer Unit as Senior Research Assistant and Mass Spec Specialist. In the period Sep 2012-June 2014 I have been involved in several LC-MS-based metabolomics projects for both internal and external collaborations. This hectic job position allowed me to span different fields of medical research, including cancer, heart disease, neuroinflammation, as well as of basic science. I have also been involved in the validation of the role of Malonyl-CoA Decarboxylase in cancer.
In October 2014 I will start my PhD in oncology in the Frezza lab. Here, I will investigate the contribution of tumour microenvironment in tumour evolution.
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. Near-complete elimination of mutant mtDNA by iterative or dynamic dose-controlled treatment with mtZFNs. Nucleic Acids Res. 2016 Jul 27. pii: gkw676. [Epub ahead of print]
Kerr EM, Gaude E, Turrell FK, Frezza C, Martins CP. Mutant Kras copy number defines metabolic reprogramming and therapeutic susceptibilities. Nature. 2016 Mar 3;531(7592):110-3. doi: 10.1038/nature16967. Epub 2016 Feb 24
Rodenhizer D, Gaude E, Cojocari D, Mahadevan R, Frezza C, Wouters BG, McGuigan AP. A three-dimensional engineered tumour for spatial snapshot analysis of cell metabolism and phenotype in hypoxic gradients. Nat Mater. 2016 Feb;15(2):227-34. doi: 10.1038/nmat4482. Epub 2015 Nov 23. Erratum in: Nat Mater. 2016 Feb;15(2):244.
Catanzaro D, Gaude E, Orso G, Giordano C, Guzzo G, Rasola A, Ragazzi E, Caparrotta L, Frezza C, Montopoli M. Inhibition of glucose-6-phosphate dehydrogenase sensitizes cisplatin-resistant cells to death. Oncotarget. 2015 Oct 6;6(30):30102-14. doi: 10.18632/oncotarget.4945
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. Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS. Nature. 2014 Nov 20;515(7527):431-5. doi: 10.1038/nature13909. Epub 2014 Nov 5.
Gaude E, Frezza C. Defects in mitochondrial metabolism and cancer. Cancer Metab. 2014 Jul 17;2:10.
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. Germline FH mutations presenting with pheochromocytoma. J Clin Endocrinol Metab. 2014 Jul 8
Sciacovelli M*, Gaude E*, Hilvo M*, Frezza C. The metabolic alterations of cancer cells. Methods Enzymol. 2014;542:1-23. *: shared contribution
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. Nuclear ARRB1 induces pseudohypoxia and cellular metabolism reprogramming in prostate cancer. EMBO J.2014 Jun 17;33(12):1365-82.
Drago D, Cossetti C, Iraci N, Gaude E, Musco G, Bachi A, Pluchino S. The stem cell secretome and its role in brain repair. Biochimie. 2013 Dec;95(12):2271-85. doi: 10.1016/j.biochi.2013.06.020. Epub 2013 Jul 1. Review.
Dr Ganesh Kadamur, Post-Doctoral Researcher
I completed my undergraduate studies at the Indian Institute of Technology Madras in India in 2008, majoring in Biotechnology with a minor in Chemistry. I spent a summer at the MRC-LMB studying chemotaxis in Dicty. For my undergraduate thesis, I applied my knowledge of modeling to the problem of caffeine degradation by soil bacterium while simultaneously learning bench skills that I then used to experimentally validate predictions from the modeling analyses.
I then moved to the US to start my PhD in Molecular Biophysics in the lab of Elliott Ross at UT Southwestern Medical Center at Dallas. Here, I used a combination of enzymology, spectroscopy and simulations to probe regulation of signaling enzymes by G proteins and understand the underlying conformational changes using novel FRET sensors.
In 2016, I joined Christian Frezza’s group as a NCBS-InStem-Cambridge fellow. Here, I will be looking at the contribution of mitochondrial dysregulation towards cancer. Specifically, I will be designing biosensors for critical molecules that are thought to be oncometabolites and elucidating the mechanisms by which various signaling pathways regulate mitochondrial function.
Kadamur, G. and Ross, E.M. (2016) Intrinsic PH domain motion in PLC-b exposes a Gbg binding site. J. Biol. Chem., 291: 11394-11406. doi: 10.1074/jbc.M116.723940
Kadamur, G. and Ross, E.M. (2013) Mammalian Phospholipase C. Ann. Rev. Physiol., 75:127-154. doi: 10.1146/annurev-physiol-030212-183750.
Philip, F., Kadamur, G., González Silos, R., Woodson, J. and Ross, E.M. (2010) Synergistic activation of phospholipase C-b3 by Gaq and Gbg describes a simple two state coincidence detector. Curr. Biol., 20:1327-1335. doi: doi: 10.1016/j.cub.2010.06.013.
Current Visiting Scientists and Students:
Angel Merchan (Amgen Scholar, summer 2015)
Sebastian Theobald (Erasmus student, summer 2015)
Susana Barros (Leonardo Da Vinci Fellow, summer 2013; now PhD student at the IRB, Barcelona)
Daniela Catanzaro (visiting post-doc, summer 2012; now post-doc in the laboratory of Monica Montopoli, Dept. Pharmaceutical and Pharmacological Sciences, University of Padova)
Prodromos Chatzikyriakou (Wellcome Trust internship, summer 2013)
Andrei Cimpan (Erasmus student, summer 2013)
Mika Hilvo (visting post-doc, 2012-2013; now scientist at Zora Biosciences Ltd)
Andrew Lawson (University of Cambridge Part III biochemistry student, summer 2012; now PhD student at Harvard University)
Christine Leon (Whitaker International Summer Award student, summer 2013; now PhD student at Berkley University)
Benedikt Rechmann (Summer student, 2015. Came to the group as an intern from the Masters Program in Molecular Biosciences, Heidelberg University International).
Sandra Abbo (Erasmus student from Wageningen University, The Netherlands).
Frezza Group: July 2016
Frezza Lab Retreat: June 2016
Frezza Lab: Christmas 2015.
Frezza Lab: February 2015.
Frezza Lab Retreat: Cromer 2015.
Frezza Lab Day Out: 2014