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Group Members

Group Leader: Dr Christian Frezza

 

Ashley Ferguson, MPhil Student

While pursuing a cancer research project at the Loudoun Academy of Science in 2011, my collaborators from Hwa Chong Institution, Singapore and I stumbled on literature describing metabolic alterations in cancer.  Since then, I have been interested in understanding why cancer cells exhibit a hallmark of metabolic rewiring.  While completing my undergraduate degree at the University of Virginia, I worked in the lab of David Kashatus, Ph.D. (2013-2017) studying how mitochondrial behaviour is altered in the context of changing nutrient environments.  Here, I became interested in how dysregulation of mitochondrial dynamics might contribute to changes in cell metabolism.

In the Frezza lab, I will continue to investigate the relationship between mitochondrial form and function during my master’s.  I am grateful for support from Rotary International on this project.


 

Lucas Anthony Maddalena, PhD Student

I previously obtained Honours BSc (Biomedical Sciences) and MSc (Cell & Molecular Biology) degrees at Brock University (St. Catharines, Ontario) in my home country of Canada. My research interests include understanding the interaction between mitochondrial function and cellular metabolism as they pertain to normal and aberrant cell biology.

 Beginning in my third year of undergraduate studies, I worked for eight months as a laboratory Research Assistant investigating the molecular basis of metabolic rate allometry in mammalian cells. Subsequently, I completed an eight month-long fourth year laboratory thesis project. For this, I developed a hypoxic cell culture system that allowed me to investigate the efficacy of a novel mitochondrial-targeted apoptosis inhibitor (‘TPP-IOA’) in the prevention of cell death caused by hypoxia/re-oxygenation. Subsequently, for my MSc thesis I investigated how TPP-IOA interacts with components of the mitochondrial oxidative phosphorylation machinery and assessed its effects on aspects of both mitochondrial physiology and cellular metabolism. Following completion (Sept. 2016), I remained at Brock University for one year as a Research Associate in the lab of my BSc and MSc supervisor, Dr. Jeffrey Stuart. I focused mainly on deciphering relationships between pericellular oxygen levels, reactive oxygen species levels, energy metabolism, & mitotic division in cultured proliferative cells. As a strong believer of collaboration in scientific research, dating back to my MSc studies I have consistently utilized my cell/molecular biology & microscopy skills in collaborative projects with a diverse set of researchers/academics, including developmental biologists, skeletal muscle physiologists, organic chemists, physicists, & a poet.

 In Winter 2017, I received a 2017 CRUK Cambridge Centre PhD Studentship to pursue doctoral studies under the joint supervision of Prof. Margaret Ashcroft (Dpt. of Medicine) and Dr. Frezza. Beginning in October 2017, I will investigate the role of hypoxia inducible factor signaling in tumorigenesis driven by fumarate hydratase deficiency. I am both extremely excited to join both groups and very much looking forward to the journey ahead!

 

Selected publications:

Maddalena LA, Selim SM, Fonseca J, Messner H, McGowan S, Stuart JA. Hydrogen peroxide production is affected by oxygen levels in mammalian cell culture. Biochem Biophys Res Commun. In press. 2017 Sep 9. pii: S0006-291X(17)31797-7. doi: 10.1016/j.bbrc.2017.09.037. [Epub ahead of print].

 Valente JA, Maddalena LA, Robb EL, Moradi F, Stuart JA. A simple ImageJ macro tool for analyzing mitochondrial network morphology in mammalian cell culture. Acta Histochem. 2017 Apr;119(3):315-326. doi: 10.1016/j.acthis.2017.03.001. Epub 2017 Mar 15.

 Maddalena LA, Ghelfi M, Atkinson J, Stuart JA. The mitochondria-targeted imidazole substituted oleic acid 'TPP-IOA' affects mitochondrial bioenergetics and its protective efficacy in cells is influenced by cellular dependence on aerobic metabolism. Biochem Biophys Acta. 2017 Jan;1858(1):73-85. doi: 10.1016/j.bbabio.2016.11.005. Epub 2016 Nov 9.

 Stuart JA, Maddalena LA, Merilovich M, Robb EL. A midlife crisis for the mitochondrial free radical theory of aging. Longev Healthspan. 2014 Apr 1;3(1):4. doi: 10.1186/2046-2395-3-4.


 

Christina Schmidt, PhD Student

I started studying biochemistry at the Julius-Maximilians University of Würzburg (Germany) in 2011. During my Bachelor’s I gained a solid knowledge foundation in the field of biochemical sciences but I also developed a keen interest in tumor biology writing my bachelor thesis about “The role of the mitotic cell-cycle protein MPS1 during TMZ-treatment of GBM”.

After my graduation in 2014, I continued with my studies in biochemistry by taking part in the master’s program at the same university. My first year I spent at the University of Oulu (Finland) with the Erasmus program. This time abroad not only faced me with darkness and freezing temperatures but also with interesting lectures and a great research-stay in the laboratory of Prof. Seppo Vainio where I worked on the project of Dr. Mirja Krause focusing on the investigation of the role of extracellular vesicles during kidney morphogenesis. Back in Germany, I focused on molecular and clinical oncology, RNA-sciences and tissue engineering. Besides taking part in the different lectures I started an internship at the Fraunhofer Institute of Tissue Engineering and Regenerative Medicine Würzburg (Germany). In the group of Dr. Marco Metzger my task was to optimize a co-culture model system including human colon adenocarcinoma cells and primary DC’s. Moreover, I gained insight into the field of rheology by mimicking the physiological environment of the chymus.

My aim to analyse the metabolic rewiring of cancer cells in the field of cancer metabolism I discovered as part of my lectures and seminars with Prof. Almut Schulze (Biocenter Würzburg, Germany), where I later wrote my master thesis. But before I started my thesis, I was working in the group of Dr. Christian Frezza at the MRC Cancer Unit Cambridge (UK), which gave me the chance to learn more about the general metabolic rewiring, but also to explore new tools such as LC-MS and the Seahorse Analyser.

In July 2017 I finished my master’s degree with my thesis about the “Regulation of cancer cell metabolism by PFKFB4”.  During my thesis, I isolated mouse embryonic fibroblasts harbouring an PFKFB4 flx-system, which I characterised via genomic PCR, qPCR, mass spectrometry and Fru-6-P-Assay.

In October 2017 I started my PhD under the Marie Sklodowska-Curie [ITN] Early Stage Researcher Fellowship “TRANSMIT – TRANSlating the role of Mitochondria in Tumorigenesis” in the laboratory of Dr. Christian Frezza. The project focuses on the understanding of the role of the mitochondrial enzyme Fumarate Hydratase in tumorigenesis.


 

Dr Marco Sciacovelli, Post-Doctoral Researcher

marco1

 

 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.

 

Recent publications

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 

 vin1I 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.

 

Recent publications

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 CostaMass Spectrometry Specialist 

Sofia Costa CF lab

 

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


 

Edoardo Gaude, PhD Student 


edoardo1I 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.

 

Recent publications

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

Ganesh1I 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.

 

Recent Publications

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.


Alumni

Joelle Janssen (starting as a PhD at the Wageningen University, Netherlands)

Lorea Valcarel Jimenez (currently PhD student at the CIC bioGUNE, Spain; FEBS visiting fellow, spring 2017)

Isaac Johnson (currently post-doc at the CRUK CI)

Ashley Ferguson (currently at the University of Virginia, Charlottesville; visiting student, summer 2016)

Patrycja Krawczyk (currently at the University of Wurzburg; visiting student, summer 2016 )

Christina Schmidt (currently at the Adam Mickiewicz University in Poznań; visiting student, summer 2016 )

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).

Alizee Vercauteren.

Sandra Abbo (Erasmus student from Wageningen University, The Netherlands).

Inge Wortell.