TRANSMIT - TRANSlating the role of Mitochondria in Tumorigenesis
The consolidation of the knowledge that cancer is not only a genetic, but also a metabolic disease, has led scientists to investigate the intricate metabolic plasticity that transformed cells must undergo to survive the adverse tumor microenvironment conditions, and the contribution of oncogenes and tumor suppressors in shaping metabolism. In this scenario, genetic, biochemical and clinical evidences place mitochondria as key actors in cancer metabolic restructuring, not only because these organelles have a crucial role in the energy and biosynthetic intermediates production but also because occurrence of mutations in metabolic enzymes encoded by both nuclear and mitochondrial DNA has been associated to different types of cancer. TRANSMIT aims to dissect the metabolic remodeling in human cancers, placing the focus on the role of mitochondria and bridging basic research to the improvement/development of therapeutic strategies. Further, TRANSMIT fosters the communication of this emerging field to the patients and their families. To these aims, TRANSMIT will create a network of seven different countries, among which world-leading basic science and clinical centers of excellence, several industrial partners with up-todate omics technologies, as well as non-profit foundations and associations who care for cancer patients. By creating the critical mass of scientific excellence, TRANSMIT will allow to transfer the current knowledge into the wide field of cancer research, translating scientific and technical advances into the education and training of eleven Early Stage Researchers. TRANSMIT will implement training-through-research dedicated to unravel the metabolic features of cancer, as well as to provide a full portfolio of complementary skills through the creation of a network of basic, translational and industrial laboratories, devoted to a multidisciplinary/multisectorial education of young scientists.
ESR (Early Stage Researcher) position for 36 months at Medical Research Council Cancer Unit, University of Cambridge, Cambridge, UK
The Frezza laboratory focuses on understanding the role of the mitochondrial enzyme and component of the tricarboxylic acid (TCA) cycle Fumarate Hydratase in tumorigenesis. We have recently demonstrated that fumarate, accumulated in FH-deficient cells, elicits a powerful epigenetic reprogramming that leads to the suppression of miRNA200, and induction of epithelial–to-mesenchymal transition (Sciacovelli et al, Nature 2016). This epigenetic and phenotypic switch makes FH-deficient cells more motile and invasive, predisposing to metastasis. Although we demonstrated that fumarate has a role as epigenetic modifier, its effects on chromatin structure and function are still unknown. This project will help to elucidate the link between TCA cycle dysfunction, accumulation of fumarate, and downstream epigenetic changes involved in tumorigenesis. To this aim the ESR will investigate the hypothesis that fumarate controls the activity of histone and DNA demethylases involved in DNA and histone methylation, causing broad epigenetic changes. The ESR will first generate a 3D cellular model of FH-deficiency by deleting FH in human renal cell lines obtained using CRISPR technology. He/she will then perform comprehensive subcellular metabolomics analyses to study the metabolic changes induced by the loss of FH in a compartment-specific manner, focusing in particular on the accumulation of fumarate in the nucleus. Then, the ESR will perform an extensive epigenetic analysis aimed at understanding how fumarate modulates genes expression and chromatin structure by altering DNA methylation and histone marks deposition. To assess DNA methylation, genome scale bisulfite sequencing and liquid chromatography analyses will be performed. Further, ESR will also perform Chip-bisulfite sequencing analyses to evaluate changes in histones binding to chromatin and their association to methylated DNA. These epigenetic changes will be merged with RNA-seq experiments to find the link between epigenetic modification and gene expression.
Subject area of PhD program in which the ESR will be enrolled and PhD program duration: 3-year enrollment to a PhD Medical Science
Host University that will provide the PhD degree: University of Cambridge
PhD program starting date: 01/10/2017
Required Educational Level
Degree: Applicants should hold a Masters level Degree in Biological Sciences in the field of Biochemistry, Cell Biology, or Cancer Biology.
Skills: The ideal candidate should be familiar with the field of cancer metabolism and have a clear understanding of cellular metabolism and mitochondrial physiology. He/she will have proven experience with cell culture and several lab techniques, including western blotting, molecular biology. The ideal candidate should also be familiar with the basics bioinformatics tools and be familiar with software for data analysis. A distinct advantage will be previous experience with metabolomics experiments and work in the field of caner metabolism, and familiarity with epigenetics.
Additional requirements: Team spirit, good communication skills, and trans-national mobility
Eligibility: The applicants must be in possession of a degree in Biological sciences at the date of recruitment
- an ‘early stage researcher’ (i.e. in the first four years of his/her research career and not have a doctoral degree). The applicants must not have resided in the country where the research training activities take place for more than 12 months in the 3 years immediately prior to the recruitment date and not have carried out their main activity (work, studies, etc.) in that country.
The applicant may be a national of a Member State, of an Associated Country or of any other Third Country.
• Enrollment in a PhD school in Medical Science
• 3-year employment contract and a salary of 44,895 Euro per annum augmented by a mobility allowance of 7,200 Euro per annum
• A highly multidisciplinary, cross-cultural and competitive training program in the field of metabolism in cancer
• Secondments and a specific training program
• Vacation days/year: 33 days + bank holidays
Applications, in English, should include a CV, a covering letter, detailed academic transcripts, a copy of the master’s thesis and a letter of reference - all to be submitted by email to Christine Fox (cf208@MRCCU.cam.ac.uk). Application deadline: 30 April 2017.
First selection step: Curriculum evaluation. Numerical scores will be awarded for various grading criteria such as study marks obtained, duration of study, scientific publications in peer reviewed journals, reference letter. Only those candidates who are shortlisted from this step will be contacted by e-mail for the second selection step.
Second selection step: Skype or face-to-face interviews in which candidates will be required to give a short presentation of their master’s thesis and to discuss a scientific paper that they will receive before the interview. The interview panel will include the principal investigator and other members of the host laboratory.