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Group Members

Group Leader: Dr Christian Frezza

 

 

Cissy Yong, Wellcome Trust PhD for Clinicians - Training Fellow

I obtained my MBBS and intercalated BSc in Surgical Sciences from University College London in 2014. It was here I gained my first taste for hypothesis-driven science through investigating the role of toll-like receptors in critical limb ischaemia with the Vascular Research Unit, Royal Free Hospital, London. This galvanised my pursuit for integrating research with clinical training, leading me to obtain jobs as a General Surgery Academic Foundation Doctor and later as a Urology Academic Clinical Fellow.

 During this time, in conjunction with Mr. Grant Stewart (University Lecturer in Urological Surgery, University of Cambridge (https://surgery.medschl.cam.ac.uk/staff/stewart/)) and Dr. Christian Frezza, I developed an interest in understanding how kidney cancer, the 7th most common UK cancer and the most lethal of urological malignancies, manipulates physiological metabolism to evolve and advance in a manner that surpasses our current understanding and treatment options available to tackle this important disease process. As a urological trainee, I am interested in bringing the bench closer to the bedside, closing in on some of the gaps in translational medicine, through the development of novel surgical models to study kidney cancer metabolism.

 With support from the Fulbright-The Urology Foundation Scholarship award, I spent three months in the world-renowned metabolomics lab of the DeBerardinis Group, UT Southwestern Medical Centre, Texas, learning the gold-standard techniques in conducting in vivo isotopic tracer studies in both human and patient-derived xenograft models for the evaluation of dynamic cancer metabolism. This invaluable experience laid the foundations for me commencing my Wellcome Trust PhD for Clinicians Training Fellowship in Oct 2018, under the joint supervision of Grant Stewart and Christian Frezza. Capitalising on the breadth of patients with kidney cancer at Cambridge University Hospitals, one of the highest volume kidney cancer and oncology services in the UK, in conjunction with the Frezza lab, a world-leading cancer metabolomics lab, my overall aim is to develop the use of isotopic tracers to investigate in vivo dynamic metabolism in this broad cohort of surgical patients with kidney cancer, as well as develop novel synergistic translatable platforms through the concurrent use of human tissues. Ultimately, understanding the intricacies of metabolic reprogramming in kidney cancer will enable us to exploit these vulnerabilities for clinical and therapeutic applications.

 


 

Connor Rogerson, Research Associate

 I started studying biochemistry at Newcastle University in 2012. I knew from an early stage that I wanted to get into research, so I obtained funding for a summer project with Dr Jeremy Brown to investigate the role of RNA surveillance machinery in post-transcriptional RNA processing of non-coding RNAs in yeast. After a summer of northern blots, RT-PCRs and sequencing, my mind was set on a career of research. In my 3rd year research project I worked with Dr Rakesh Heer looking into putative prostate stem cells and the involvement of Notch signalling proteins as molecular markers.

 During my degree I developed a keen interest in how genes work, specifically their role in disease. I landed a PhD position in Prof Andy Sharrocks’ lab at the University of Manchester researching the role of chromatin and transcription factors in the deadly disease of oesophageal cancer. It was here that I became a true epigenetics junkie by learning the art of next generation sequencing to profile open chromatin (ATAC-seq), DNA-binding of transcription factors (ChIP-seq) and expression of genes (RNA-seq).

 After my PhD, I wanted to broaden my horizons to new fields, but still with an epigenetics flavour. After a soul-searching exercise I decided to pursue a position with Dr Christian Frezza where I will be working on how the loss of FH, and increased fumarate can affect gene expression in cancer, and the mechanisms behind this.

 https://orcid.org/0000-0002-1425-9668

 Publications:

 Rogerson C, Britton E, Withey S, Hanley N, Yeng AS, Sharrocks AD (2019), Identification of a Primitive Intestinal Transcription Factor Network Shared Between Esophageal Adenocarcinoma and Its Precancerous Precursor State. Genome Res, 29 (5), 723-736

 Baker SM, Rogerson C, Hayes A, Sharrocks AD, Rattray M (2019), Classifying Cells With Scasat, a Single-Cell ATAC-seq Analysis Tool. Nucleic Acids Res, 47 (2), e10

 Pegg HJ, Harrison H, Rogerson C, Shore P (2019), The RUNX Transcriptional Coregulator, CBFβ, Suppresses Migration of ER + Breast Cancer Cells by Repressing ERα-Mediated Expression of the Migratory Factor TFF1. Mol Cancer Res, 17 (5), 1015-1023

 Britton E, Rogerson C, Mehta S, Li, Y, Li X, OCCAMS consortium, Fitzgerald RC, Ang YS, Sharrocks AD (2017), Open Chromatin Profiling Identifies AP1 as a Transcriptional Regulator in Oesophageal Adenocarcinoma. PLOS Genetics, 13 (8), e1006879


Tim Young, Research Assistant

I qualified as a Biomedical Scientist in 2012 after completing my bachelor’s degree at The University of Essex but never entered practise. Instead I moved towards research

As part of my integrated biomedical science degree at the University of Essex, I completed my training year in Clinical Biochemistry department at Addenbrooke’s, performing routine and specialist patient tests. After my degree I moved towards research and my first job was a technician with the MRC Epidemiology Unit, here I used a variety of methods to perform batch analysis of large cohorts of samples.

After this I moved towards cancer research and worked as a research assistant for Prof. Bruce Ponder in conjunction with the NHS Papworth Histology team. The research was directed towards the investigation of DNA repair dysfunction which can cause a genetic predisposition to lung cancer, particularly in smokers.

Then, in 2016, I joined the labs of Christian Frezza and Thomas Krieg working on multiple projects as part of the Mitochondrial Therapy Group (MTG) before beginning my current role solely with Dr. Frezza.

  

 


Dylan Ryan, Research Associate

 DylanI obtained my Bachelor of science (BSc) in Biochemistry from University College Dublin (UCD) in 2015. During my studies, I developed a real passion for metabolism and in trying to understand how dysregulation of metabolic pathways can lead to disease. My interest in metabolism and disease motivated me to pursue a summer studentship and final year research project in the lab of Dr. Gethin McBean. During my time in Dr. McBean’s lab, I examined the functionality of cystine and glutamate transport systems and the glutathione-antioxidant pathway in an in vitro model of cystinosis, a rare genetic lysosomal storage disease. Specifically, I examined these systems in C6 glioma cells and immortalised bone-marrow derived macrophages, which were used as a model of astrocytes and microglia, respectively. This pilot project represented the first attempt to understand the molecular underpinnings of cerebral dysfunction in cystinosis.

I also developed a keen interest in macrophage biology and immunology during my summer studentship and was fortunate to come across the work of Prof. Luke O’Neill in Trinity College Dublin, who remarkably at the time had demonstrated a role for glycolysis and succinate in the regulation of cytokine production in macrophages. This link between metabolism and immune cell function was a seminal discovery in a brand-new field of immunological research termed ‘immunometabolism’ and prompted me to pursue a PhD in his laboratory. During my time in Prof. Luke O’Neill’s lab, I investigated the role of Krebs cycle rewiring in the regulation of macrophage cytokine production, with a particular focus on the Krebs cycle metabolite fumarate and the Krebs cycle-derived metabolite itaconate. Recently from this work, I uncovered a novel role for itaconate as a critical anti-inflammatory metabolite that can activate the anti-inflammatory transcription factor Nrf2 in macrophages. Furthermore, we found that itaconate is a mildly electrophilic metabolite that can irreversibly modify protein cysteine residues, a wholly novel post-translational modification termed 2,3-dicarboxypropylation, akin to fumarate-mediated protein succination. I will defend my PhD thesis titled ‘Analysis of the role of Krebs cycle rewiring in macrophage cytokine production’ in October 2019.

Throughout my PhD, I collaborated closely with the laboratory of Dr. Christian Frezza where all of my metabolomics samples were analysed. This collaboration, along with my longstanding interest in the role of metabolism in disease, led me to pursue a research associate position in the Frezza lab where I will be investigating how FH-deficient tumours and fumarate regulate macrophage function in the tumour microenvironment.

 First author publications:

 

  1. Ryan D, Murphy M, Frezza C, Prag H, Chouchani E, O’Neill L et al. Coupling Krebs cycle metabolites to signalling in immunity and cancer. Nature Metabolism. 2018;1(1):16-33.
  2. Mills E*, Ryan D*, Prag H, Dikovskaya D, Menon D, Zaslona Z et al. Itaconate is an anti-inflammatory metabolite that activates Nrf2 via alkylation of KEAP1. Nature. 2018;556(7699):113-117.*Joint-first
  3. Ryan D, O'Neill L. Krebs cycle rewired for macrophage and dendritic cell effector functions. FEBS Letters. 2017;591(19):2992-3006.

 Other publications:

 

  1. Mills E*, Kelly B*, Logan A, Costa A, Varma M, Bryant C et al. Succinate Dehydrogenase Supports Metabolic Repurposing of Mitochondria to Drive Inflammatory Macrophages. Cell. 2016;167(2):457-470.e13.*Joint-first
  2. Hughes M*, Lavrencic P*, Coll R, Ve T, Ryan D, Williams N et al. Solution structure of the TLR adaptor MAL/TIRAP reveals an intact BB loop and supports MAL Cys91 glutathionylation for signaling. Proceedings of the National Academy of Sciences. 2017;114(32):E6480-E6489.*Joint-first
  3. Early J, Menon D, Wyse C, Cervantes-Silva M, Zaslona Z, Carroll R et al. Circadian clock protein BMAL1 regulates IL-1β in macrophages via NRF2. Proceedings of the National Academy of Sciences. 2018;115(36):E8460-E8468.
  4. Olagnier D, Brandtoft A, Gunderstofte C, Villadsen N, Krapp C, Thielke A et al. Nrf2 negatively regulates STING indicating a link between antiviral sensing and metabolic reprogramming. Nature Communications. 2018;9(1).
  5. Baardman J, Verberk S, Prange K, van Weeghel M, van der Velden S, Ryan D et al. A Defective Pentose Phosphate Pathway Reduces Inflammatory Macrophage Responses during Hypercholesterolemia. Cell Reports. 2018;25(8):2044-2052.e5.

Ariane Mora, Research Associate

I completed my undergraduate honours degree in Electrical and Computer Engineering at the University of Queensland in 2019. Following the completion of my degree, I joined the Boden lab at the University of Queensland working on ancestral sequence reconstruction. Shortly after, I commenced a PhD in July of 2019, under the supervision of A. Prof. Mikael Boden and A. Prof. Jessica Mar. My interest is in exploring methods for integrating data, specifically developing models that are able to capture the stochastic, dynamic nature of biological systems. As of April 2020, I am collaborating with Dr Frezza’s lab and applying non-linear methods to develop integrative models of FH deficient cells.

 

 

 


 

Ming Yang, Research Associate

 

I studied chemistry as an undergraduate at Peking University in China, after which I obtained an MPhil degree in Organic Chemistry from University of Cambridge in 2005. In 2006 I joined the laboratory of Prof Chris Schofield at University of Oxford, where I worked on the substrate selectivity of the HIF asparaginyl hydroxylase FIH and obtained a DPhil in Organic Chemistry in 2010. After a brief postdoc at the Welcome Trust Centre of Human Genetics working on HIF prolyl hydroxylases, I moved to the cancer metabolism field, to work on fumarate hydratase-deficient cancer HLRCC with Dr Patrick Pollard at the University of Edinburgh. I then had the great pleasure to work with Prof. Karen Vousden from 2015 to 2019 on the metabolic role of the TP53-induced glycolysis and apoptosis regulator TIGAR in cancer, first at the Beatson Institute of Cancer Research in Glasgow and then at the Francis Crick Institute in London. After recognizing my passion for metabolic research and instrumentation, I joined the Frezza lab mass spec facility in March 2020, to provide technical and scientific support in metabolomics to both lab members and external collaborators.

 


 

Lorea Valcarcel, Visiting Research Fellow

I obtained my degree in Biochemistry and Molecular Biology by the University of the Basque Country in 2012. During this period, I had the opportunity to study the breakage mechanism of the BCL2 gene in the (14;18) translocation, that occurs in Follicular Lymphomas (Department of Genetics, Faculty of Medicine).

Lorea

Aiming to understand the translational content of my degree, I decided to move to Barcelona and start a master degree in Molecular Biotechnology. I joined the Regulation of Lipid Metabolism Group (School of Pharmacy, University of Barcelona), where I studied the link between circadian rhythm alterations and lipid metabolism. Thanks to the project and to my supervisor Laura Herrero, I became a metabolism lover.

When having to decide which topic to choose for my PhD I had it clear. During many years I have always had a question in mind: how normal cells rewire their metabolic and genetic landscape in order to become tumoral? Because of this, in 2014 I decided to start my PhD in Arkaitz Carracedo’s lab under his and Veronica Torrano´s supervision. During four years I was focused on deciphering the transcriptional control of metabolism during prostate cancer pathogenesis and progression, and the molecular and cellular consequences underlying that regulation. As a result of this study, we demonstrated that the transcriptional program driven by PGC1A opposes cancer aggressiveness and metastatic dissemination. Moreover, and thanks to the use of human cancer datasets, we were able to stablish correlations between gene signatures and the aggressiveness of the disease, this being of great relevance as a prognostic tool. During my PhD I also had the chance to do two short-stays that were fundamental for my 

development as a scientist. The first one was in King’s College London in Victoria Sanz Moreno lab (now in Barts Cancer Institute), studying cell motility, migration and invasion in 3D collagen matrixes. The second one was in Christian Frezza´s lab, trying to decipher the effect of mitochondrial metabolism in prostate cancer. In December 2017 I finished my PhD and continue in Carracedo´s lab until 2018 as a postdoctoral fellow, studying the transcriptional program activated by MITF in prostate cancer and the invasive mechanisms and cytoskeleton rearrangements that occur in prostate cancer cells.

In 2019 I join the Frezza´s lab to study the oncogenic events that occur in FH deficient cells and the role that mitocondrial dysfunction could have in tumorigenesis.

http://www.researcherid.com/rid/F-6747-2017


Annie Howitt, PhD student

I obtained my Bachelor's degree in Biochemistry from Imperial college London in 2018, which included a number of laboratory projects. After my first year of study, I learned the basics of molecular cloning in the Crisanti Lab at Imperial, whose objective was to engineer a sex bias in mosquitoes.

AnnieIn the third year of my studies I completed a year in research placement in Paul Huang’s lab at the Institute of Cancer Research. In this project working alongside PhD student Simon Vyse, I focused on understanding functional pathway dependencies in intrinsic resistance to EGFR inhibitor therapies in non small cell lung cancer. This involved developing a CRISPR interference platform to study synthetic lethal candidates.

I took the opportunity in my final year of teaching to focus my studies on metabolic network engineering, cancer and glycobiology. Finally, as a 10 week project culminating in my undergraduate dissertation, I worked on the characterisation of the bovine innate immune system receptor, Dectin-1 in the laboratory of Professor Kurt Drickamer and Maureen Taylor. From these experiences, I focused my interest on biological networks, cancer biology and signalling.

Currently I am a joint PhD student in both the Frezza and Esposito labs, working towards using microscopy techniques to investigate the interaction of metabolism and signalling in the setting of mitochondrial dysfunction and in KRAS mutant cancers.


 

Efterpi Nikitopoulou, Research Assistant

I obtained my bachelor’s degree on Biochemistry and Biotechnology from the University of Thessaly, in Greece, on 2015. There, I gained knowledge on general biology, analytical and organic chemistry and biochemistry. Soon, I realized my passion for studying the mechanisms underlying human diseases. Therefore, I conducted my undergraduate research project on population genetics and focused on TLR4, the most studied receptor of the innate immune system, and the frequencies of two TLR4 polymorphisms in the Greek population.

To enrich my knowledge of Genetics, I followed a master’s course on Molecular Genetics and Diagnostics at the University of Nottingham, from where I graduated on 2016 with Distinction. My master’s provided me insight on microbiology, molecular basis of genetic disorders, molecular services in health care and gene regulation in mammalian cells. My thesis research project related to the identification of a cell factory that could be used for the bioproduction of isoprene using CO2. During the course, I developed an interest on metabolism and cancer, and I was very excited to discover the laboratory of Dr Christian Frezza where I have been working as a Research Assistant 


 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 

 vin1
I obtained my degree in Biochemistry from Liège, Belgium in 1992. After a short spell doing compulsory military service in Germany, I was awarded a three-year grant 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 kit 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 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 that regulates JNK activity and apoptosis in Drosophila.

Having not had enough of Notch by then, I was fortunate to be offered a post-doc position in the laboratory of Dr Phil Jones within the Cancer Unit at the Hutchison/MRC Research Centre in Cambridge. In collaboration with Dr Doug Winton’s lab at Cambridge Institute for Medical Research, 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.

Following 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, I returned to cancer research as a post-doc in the laboratory of Professor David Neal in the Oncology Department at the CRUK Cambridge 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, where I study the role of metabolic alterations in tumorigenesis. My current projects include tissue-specific metabolic reprogramming in tumorigenesis as a consequence of mitochondrial dysfunction. My aim is to understand the early events associated with loss of Fumarate Hydratase (FH), an enzyme of the TCA cycle that is associated with the development of an aggressive kidney cancer syndrome termed Hereditary leiomyomatosis and Renal Cell Cancer (HLRCC) with the purpose to develop chemo-preventive interventions to target mutant cells early in neoplastic transformation, thus preventing cancer development. In order to do so, I developed novel animal models of FH deficiency. I am also interested in how FH-deficient tumours impact the tumour microenvironment; with a special interest in the immune response.

Warren AY, Massie CE, Watt K, Luko K, Orafidiya F, Selth LA, Mohammed H, Chohan BS, Menon S, Baridi A, Zhao W, Escriu C, Pungsrinont T, D'Santos C, Yang X, Taylor C, Qureshi A, Zecchini VR, Shaw GL, Dehm SM, Mills IG, Carroll JS, Tilley WD, McEwan IJ, Baniahmad A, Neal DE, Asim M.

A reciprocal feedback between the PDZ binding kinase and androgen receptor drives prostate cancer. (https://pubmed.ncbi.nlm.nih.gov/30237440/)

Oncogene. 2019 Feb;38(7):1136-1150. doi: 10.1038/s41388-018-0501-z. Epub 2018 Sep 20.PMID: 30237440

Asim M, Tarish F, Zecchini HI, Sanjiv K, Gelali E, Massie CE, Baridi A, Warren AY, Zhao W, Ogris C, McDuffus LA, Mascalchi P, Shaw G, Dev H, Wadhwa K, Wijnhoven P, Forment JV, Lyons SR, Lynch AG, O'Neill C, Zecchini VR, Rennie PS, Baniahmad A, Tavaré S, Mills IG, Galanty Y, Crosetto N, Schultz N, Neal D, Helleday T.

Synthetic lethality between androgen receptor signalling and the PARP pathway in prostate cancer. (https://pubmed.ncbi.nlm.nih.gov/28851861/)

Nat Commun. 2017 Aug 29;8(1):374. doi: 10.1038/s41467-017-00393-y.PMID: 28851861

Hori S, Wadhwa K, Pisupati V, Zecchini V, Ramos-Montoya A, Warren AY, Neal DE, Gnanapragasam VJ.

Loss of hSef promotes metastasis through upregulation of EMT in prostate cancer. (https://pubmed.ncbi.nlm.nih.gov/28073170/)

Int J Cancer. 2017 Apr 15;140(8):1881-1887. doi: 10.1002/ijc.30604. Epub 2017 Jan 30.PMID: 28073170

Zecchini V, Frezza C.

Metabolic synthetic lethality in cancer therapy. (https://pubmed.ncbi.nlm.nih.gov/27956047/)

Biochim Biophys Acta Bioenerg. 2017 Aug;1858(8):723-731. doi: 10.1016/j.bbabio.2016.12.003. Epub 2016 Dec 9.PMID: 27956047

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. (https://pubmed.ncbi.nlm.nih.gov/27580029/)

Nature. 2016 Aug 31;537(7621):544-547. doi: 10.1038/nature19353.PMID: 27580029

Klionsky DJ et al.

Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). (https://pubmed.ncbi.nlm.nih.gov/26799652/)

Autophagy. 2016;12(1):1-222. doi: 10.1080/15548627.2015.1100356.


Marc Segarra, Post-Doctoral Researcher

I obtained my degree in Biotechnology at the University of Barcelona (Spain) in 2014. During my studies I developed a keen interest in cell biology, in how complex regulatory pathways regulate the way in which cells respond to changes in their environment. I performed my final degree project under the supervision of Dr Francesc X. Soriano and Dr Manuel Reina (Department of Cell Biology, University of Barcelona) working on the role of synaptic activity in the regulation of neuronal metabolism. In Dr Soriano’s group, I was also able to collaborate in another project related with the study of Mfn2 in neuronal death by excitotoxicity. During that period of time I started to develop a great interest on cellular metabolism and mitochondria.

In 2015, after I obtained my Bachelor’s Degree, I performed a Master’s Degree in Biomedical Research at Pompeu Fabra University (Barcelona). In the same year I was awarded fellowship by Fundación Tatiana Pérez de Guzmán el Bueno to pursue a PhD in Neuroscience. During my PhD I kept working in Dr Soriano’s group studying the mechanisms by which synaptic activity stimulates glucose metabolism in neurons to promote neurite outgrowth. 

After finishing my PhD, in December 2019, I joined to Dr Frezza’s group to characterize the mutational signature associated with a deficiency in the enzyme Fumarate Hydratase.

 


 

 

Alumni: 

Laura Tronci (Research Associate)

Ganesh Kadamur (NCBS-InStem-Cambridge fellow)

Ana Carolina Bastos Sant’Anna-Silva, PhD student (Transmit Programme)

Houda Abla, PhD Student (Transmit Programme)

Nikkitha Umesh Ganesh, Visiting Research Fellow (Transmit Programme)

Sabarinath Peruvemba Subramanian, Post-doctoral Researcher  (currently employed at the Institute for Stem Cell Biology and Regenerative Medicine, Bangalore , in the lab of S.Ramaswamy,  in the context of the DBT-MRC programme)

Dr Sofia Costa, Mass Spectrometry Specialist (currently employed at at Cold Spring Harbour, in the laboratory of Dr Daryl Pappin) 

Ashley Ferguson, MPhil Student

Irene Herranz (Erasmus+  MPhil  student at Autonomous University of Madrid , summer 2018)

Clement Bodineau (PhD student at Institut Européen de Chimie et Biologie (IECB))

Edoardo Gaude, PhD Student (currently employed at Owlstone Medical)

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.