About the Project
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.
3-year enrollment to a PhD Medical Science from October 2017
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