Objectif Mutational heterogeneity bestows tumors with the phenotypic plasticity and adaptability required for expansion. On the other hand, mutations destabilize proteins – lower stability (metastability) of the tumor proteome must be the inevitable consequence. We set out to systematically investigate this biochemical aspect of metastasis aiming to uncover and therapeutically exploit specific vulnerabilities resulting from protein destabilization. We will approach this goal by cataloging associations between metastasis-promoting proteins and molecular chaperones. Chaperones are obvious candidates to stabilize the proteome, therefore we will prepare a BAC-based mouse model of metastasis, where the contribution of 63 chaperones, comprising the entire murine HSP70 superfamily, to metastasis development will be individually investigated. The role of metastasis-relevant chaperones at the molecular level will be elucidated using mass spectrometry, complemented by next-generation sequencing of metastatic exome. In parallel, a novel proteomics-based method to evaluate aberrant complex formation in tumor cells will be established.Because of the high heterogeneity of cancer, molecularly tailored and combined therapies are needed. To this end, we will capitalize on insights regarding the role of chaperones in metastasis by identifying proteasomal degradation activators able to support or replace the activity of individual chaperones from the HSP70 superfamily. Finally, we will validate the potential of combined, yet specific manipulation of the folding and degradation machineries to suppress metastasis development. Champ scientifique natural sciencesbiological sciencesbiochemistrybiomoleculesproteinsproteomicsnatural sciencesbiological sciencesgeneticsmutationmedical and health sciencesclinical medicineoncologynatural scienceschemical sciencesanalytical chemistrymass spectrometry Programme(s) FP7-IDEAS-ERC - Specific programme: "Ideas" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013) Thème(s) ERC-SG-LS4 - ERC Starting Grant - Physiology, Pathophysiology and Endocrinology Appel à propositions ERC-2012-StG_20111109 Voir d’autres projets de cet appel Régime de financement ERC-SG - ERC Starting Grant Institution d’accueil JOHANN WOLFGANG GOETHE-UNIVERSITAET FRANKFURT AM MAIN Contribution de l’UE € 1 366 800,00 Adresse THEODOR W ADORNO PLATZ 1 60323 Frankfurt Am Main Allemagne Voir sur la carte Région Hessen Darmstadt Frankfurt am Main, Kreisfreie Stadt Type d’activité Higher or Secondary Education Establishments Contact administratif Kristina Wege (Ms.) Chercheur principal Ramunas Martynas Vabulas (Dr.) Liens Contacter l’organisation Opens in new window Site web Opens in new window Coût total Aucune donnée Bénéficiaires (1) Trier par ordre alphabétique Trier par contribution de l’UE Tout développer Tout réduire JOHANN WOLFGANG GOETHE-UNIVERSITAET FRANKFURT AM MAIN Allemagne Contribution de l’UE € 1 366 800,00 Adresse THEODOR W ADORNO PLATZ 1 60323 Frankfurt Am Main Voir sur la carte Région Hessen Darmstadt Frankfurt am Main, Kreisfreie Stadt Type d’activité Higher or Secondary Education Establishments Contact administratif Kristina Wege (Ms.) Chercheur principal Ramunas Martynas Vabulas (Dr.) Liens Contacter l’organisation Opens in new window Site web Opens in new window Coût total Aucune donnée