Objective Chromosomal instability (CIN), the inability to correctly segregate sister chromatids during mitosis, is a hallmark of cancer cells. Overexpression of the mitotic checkpoint protein Mad2, commonly found in human tumors, leads to CIN and the development of aneuploid tumors in mouse models. However, recent observations from various laboratories suggest that aneuploidy can promote or suppress tumorigenesis. Therefore understanding the relationship between aneuploidy and tumor formation, identifying in what context aneuploidy acts oncogenically and those in which it acts as a tumor suppressor, is thus vital if we want to make progress in battling cancer. We propose to generate regulatable mouse models that recapitulate the aneuploidy state of human tumors, using state-of–the–art mouse genetic strategies, to investigate the role of CIN in promoting or suppressing tumorigenesis.Moreover, CIN has been shown to facilitate escape from oncogene addiction (the dependence of tumor cells on their initiating lesion for survival) and may be responsible for tumor relapse after targeted therapies. Due to the clinical relevance of these findings, this proposal aims to investigate how CIN potentiates oncogene independence. It is possible that some CIN cells in the primary tumor are already independent of the initiating oncogene prior to treatment. Alternatively, CIN cells are more susceptible of acquiring additional mutations and evolve to become independent of the initiating lesion. We propose to develop a highly innovative three-dimensional in vitro culture system to isolate and characterize these surviving cells to further eliminate them.It is necessary to understand the molecular mechanisms that lead to CIN and the consequences it has in tumor initiation, suppression and relapse, hoping that the genes or proteins identified could be targeted therapeutically. We believe that answers to these specific aims will have important consequences for the treatment of human tumors. Fields of science natural sciencesbiological sciencesbiochemistrybiomoleculesproteinsnatural sciencesbiological sciencesgeneticsmutationmedical and health sciencesclinical medicineoncologynatural sciencesbiological sciencesgeneticschromosomes 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) Topic(s) ERC-SG-LS4 - ERC Starting Grant - Physiology, Pathophysiology and Endocrinology Call for proposal ERC-2011-StG_20101109 See other projects for this call Funding Scheme ERC-SG - ERC Starting Grant Host institution DEUTSCHES KREBSFORSCHUNGSZENTRUM HEIDELBERG EU contribution € 958 737,05 Address IM NEUENHEIMER FELD 280 69120 Heidelberg Germany See on map Region Baden-Württemberg Karlsruhe Heidelberg, Stadtkreis Activity type Research Organisations Administrative Contact Ina Wiest (Dr.) Principal investigator Rocio Sotillo Roman (Dr.) Links Contact the organisation Opens in new window Website Opens in new window Total cost No data Beneficiaries (2) Sort alphabetically Sort by EU Contribution Expand all Collapse all DEUTSCHES KREBSFORSCHUNGSZENTRUM HEIDELBERG Germany EU contribution € 958 737,05 Address IM NEUENHEIMER FELD 280 69120 Heidelberg See on map Region Baden-Württemberg Karlsruhe Heidelberg, Stadtkreis Activity type Research Organisations Administrative Contact Ina Wiest (Dr.) Principal investigator Rocio Sotillo Roman (Dr.) Links Contact the organisation Opens in new window Website Opens in new window Total cost No data EUROPEAN MOLECULAR BIOLOGY LABORATORY Participation ended Germany EU contribution € 541 262,95 Address Meyerhofstrasse 1 69117 Heidelberg See on map Region Baden-Württemberg Karlsruhe Heidelberg, Stadtkreis Activity type Research Organisations Administrative Contact Jillian Rowe (Ms.) Links Contact the organisation Opens in new window Website Opens in new window Total cost No data