Objectif Tumors contain multiple subpopulations of cells some of which may contribute to therapeutic resistance. Moreover phenotypic states in cancer (stem-like; invasive; proliferative; and differentiated) are dynamic and reversible, yet use many of the same signaling pathways implicated in activation and self-renewal of physiological stem cells. Of these, the Wnt/b-catenin signaling pathway plays a major role in stem cell activation and differentiation, and is frequently constitutively activated in cancers. My preliminary results indicate that surprisingly, oleic acid can substitute for Wnt in activation of b-catenin signaling. Adipocytes can play a key role in stem cell activation, can transfer lipids to cancer cells, and are frequently encountered during cancer cell invasion. I hypothesize that lipid uptake by cancer cells will alter metabolism and drive phenotype-switching via b-catenin signaling. This project therefore aims to investigate the biological and metabolic consequences of lipid uptake by cancer cells and will use melanoma as a model system since the key regulators of phenotype-switching in this cancer are known to be targeted by b-catenin signaling. Specifically, I will use standard cell biology techniques to identify the repertoire of lipids able to trigger nuclear localization of b-catenin and the biological consequences of lipid uptake (invasiveness; proliferation; differentiation etc); integrative genomics (ChIP-seq and RNA-seq) to identify direct b-catenin target genes and their relationship to those targeted by the master regulator of the melanocyte lineage, MITF, that is known to interact directly with b-catenin; and metabolomics to identify how lipid uptake and de-regulation of b-catenin signaling affect cellular metabolism. The results will provide a key insight into how lipid signalling can impact on cancer biology and potentially activate physiological stem cells, as well as provide high-level training in emerging technologies. Champ scientifique natural sciencesbiological sciencesgeneticsmedical and health sciencesclinical medicineoncologyskin cancermelanomanatural sciencesbiological sciencescell biologynatural sciencesbiological sciencesbiochemistrybiomoleculeslipidsmedical and health sciencesmedical biotechnologycells technologiesstem cells Programme(s) FP7-PEOPLE - Specific programme "People" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013) Thème(s) FP7-PEOPLE-2013-IEF - Marie-Curie Action: "Intra-European fellowships for career development" Appel à propositions FP7-PEOPLE-2013-IEF Voir d’autres projets de cet appel Régime de financement MC-IEF - Intra-European Fellowships (IEF) Coordinateur THE CHANCELLOR, MASTERS AND SCHOLARS OF THE UNIVERSITY OF OXFORD Contribution de l’UE € 221 606,40 Adresse WELLINGTON SQUARE UNIVERSITY OFFICES OX1 2JD Oxford Royaume-Uni Voir sur la carte Région South East (England) Berkshire, Buckinghamshire and Oxfordshire Oxfordshire Type d’activité Higher or Secondary Education Establishments Contact administratif Gill Wells (Ms.) Liens Contacter l’organisation Opens in new window Site web Opens in new window Coût total Aucune donnée