Objectif Cancer development is characterized by uncontrolled proliferation, cell survival and metabolic reprogramming. Tumour cells are surrounded by a fluid-mosaic membrane that contains tetraspanins (Tspans) which are evolutionary conserved proteins important in the formation of multiprotein complexes at the cell surface (‘tetraspanin web’). Increasing evidence indicates that Tspans are involved in cancer, still the architecture of the Tspan web in native tumour membranes and its (patho)physiological functions have not been resolved. Based on my preliminary data, I hypothesize that tumour cells contain a disrupted Tspan web in which Tspan interactions are modified leading to aberrant metabolic signalling and tumour development. This is supported by my discovery that loss of Tspan CD37 leads to spontaneous lymphomagenesis due to activation of the Akt survival pathway. The overall aim of Secret Surface is to unravel the composition, physiological functions and molecular mechanisms of the Tspan web on tumour development and clinical outcome. To achieve this, I will focus on studying lymphomas using a multidisciplinary approach: I. Detailed analyses of Tspan web composition in lymphoma to select clinically relevant Tspans (high-throughput tissue microarray technology, multispectral imaging). II. Resolve the endogenous Tspan web on lymphoma cells (super-resolution microscopy), and generation and analysis of lymphoma cells that have a complete deficiency of multiple Tspans (CRISPR/Cas9 technology). III. Decipher molecular mechanisms underlying Tspan web function in lymphoma cells (membrane organization, membrane-proximal signalling, metabolic reprogramming). With my unique toolbox of Tspan knock-outs coupled to advanced microscopy and metabolic studies, I expect that Secret Surface will lead to a new concept in cellular physiology in which cell surface organization by the Tspan web drives tumour development, which may open new horizons for the generation of new cancer therapies. Champ scientifique natural sciencesphysical sciencesopticsmicroscopysuper resolution microscopynatural sciencesbiological sciencesbiochemistrybiomoleculesproteinsnatural sciencesbiological sciencesbiochemistrybiomoleculeslipidsmedical and health sciencesclinical medicineoncologymedical and health sciencesbasic medicinephysiology Mots‑clés Lymphoma cellular physiology plasma membrane signal transduction super-resolution imaging Programme(s) H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) Main Programme Thème(s) ERC-2016-COG - ERC Consolidator Grant Appel à propositions ERC-2016-COG Voir d’autres projets de cet appel Régime de financement ERC-COG - Consolidator Grant Institution d’accueil STICHTING RADBOUD UNIVERSITAIR MEDISCH CENTRUM Contribution nette de l'UE € 2 000 000,00 Adresse GEERT GROOTEPLEIN 10 ZUID 6525 GA Nijmegen Pays-Bas Voir sur la carte Région Oost-Nederland Gelderland Arnhem/Nijmegen Type d’activité Higher or Secondary Education Establishments Liens Contacter l’organisation Opens in new window Participation aux programmes de R&I de l'UE Opens in new window Réseau de collaboration HORIZON Opens in new window Coût total € 2 000 000,00 Bénéficiaires (2) Trier par ordre alphabétique Trier par contribution nette de l'UE Tout développer Tout réduire STICHTING RADBOUD UNIVERSITAIR MEDISCH CENTRUM Pays-Bas Contribution nette de l'UE € 2 000 000,00 Adresse GEERT GROOTEPLEIN 10 ZUID 6525 GA Nijmegen Voir sur la carte Région Oost-Nederland Gelderland Arnhem/Nijmegen Type d’activité Higher or Secondary Education Establishments Liens Contacter l’organisation Opens in new window Participation aux programmes de R&I de l'UE Opens in new window Réseau de collaboration HORIZON Opens in new window Coût total € 2 000 000,00 STICHTING RADBOUD UNIVERSITEIT Participation terminée Pays-Bas Contribution nette de l'UE € 0,00 Adresse HOUTLAAN 4 6525 XZ Nijmegen Voir sur la carte Région Oost-Nederland Gelderland Arnhem/Nijmegen Type d’activité Higher or Secondary Education Establishments Liens Contacter l’organisation Opens in new window Site web Opens in new window Participation aux programmes de R&I de l'UE Opens in new window Réseau de collaboration HORIZON Opens in new window Coût total Aucune donnée
