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Defining the Impact of Chromosome Instability in Tumor Initiation, Maintenance and Relapse

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.

Call for proposal

ERC-2011-StG_20101109
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Host institution

DEUTSCHES KREBSFORSCHUNGSZENTRUM HEIDELBERG
Address
Im Neuenheimer Feld 280
69120 Heidelberg
Germany
Activity type
Research Organisations
EU contribution
€ 958 737,05
Principal investigator
Rocio Sotillo Roman (Dr.)
Administrative Contact
Ina Wiest (Dr.)

Beneficiaries (2)

DEUTSCHES KREBSFORSCHUNGSZENTRUM HEIDELBERG
Germany
EU contribution
€ 958 737,05
Address
Im Neuenheimer Feld 280
69120 Heidelberg
Activity type
Research Organisations
Principal investigator
Rocio Sotillo Roman (Dr.)
Administrative Contact
Ina Wiest (Dr.)
EUROPEAN MOLECULAR BIOLOGY LABORATORY

Participation ended

Germany
EU contribution
€ 541 262,95
Address
Meyerhofstrasse 1
69117 Heidelberg
Activity type
Research Organisations
Administrative Contact
Jillian Rowe (Ms.)