Cel 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 depending on the context. This proposal aims to understand the relationship between aneuploidy and tumor formation and to identify in what context aneuploidy acts oncogenically and those in which it acts as a tumor suppressor. We propose to generate inducible mouse models that recapitulate the aneuploidy state of human tumors, to investigate the role of CIN in promoting or suppressing cancer.In addition, we have shown that CIN facilitates 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, we will 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 will develop an innovative three-dimensional in vitro culture system to isolate and characterize surviving cells after de-induction of the transgenes. 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.Finally, if human tumors are characterized by an overactive checkpoint we should validate the therapeutic potential of acute downregulation of mitotic checkpoint function in vivo. Dziedzina nauki natural sciencesbiological sciencesbiochemistrybiomoleculesproteinsnatural sciencesbiological sciencesgeneticsmutationmedical and health sciencesclinical medicineoncologynatural sciencesbiological sciencesgeneticschromosomes Program(-y) FP7-PEOPLE - Specific programme "People" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013) Temat(-y) FP7-PEOPLE-2011-CIG - Marie-Curie Action: "Career Integration Grants" Zaproszenie do składania wniosków FP7-PEOPLE-2011-CIG Zobacz inne projekty w ramach tego zaproszenia System finansowania MC-CIG - Support for training and career development of researcher (CIG) Koordynator EUROPEAN MOLECULAR BIOLOGY LABORATORY Wkład UE € 100 000,00 Adres Meyerhofstrasse 1 69117 Heidelberg Niemcy Zobacz na mapie Region Baden-Württemberg Karlsruhe Heidelberg, Stadtkreis Rodzaj działalności Research Organisations Kontakt administracyjny Jillian Rowe (Ms.) Linki Kontakt z organizacją Opens in new window Strona internetowa Opens in new window Koszt całkowity Brak danych
