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Tumour Heterogeneity and Somatic Evolution of Unstable cancer genomes

Objectif

Summary
The majority of metastastic solid tumours remain incurable. In-depth analysis of tumour genomes is revealing evidence for branched evolution and cancer subclonal spatial and temporal intratumour heterogeneity (ITH). Drivers of ITH such as chromosomal instability (CIN) are associated with drug resistance and poor clinical outcome. However, despite increasing knowledge of tumour diversity, there is limited insight into the mechanisms driving genomic instability and ITH or the processes that shape cancer genome evolution over time and space. Many animal tumour models fail to recapitulate patterns of genomic instability witnessed in human tumours, limiting insight into the forces that shape tumour evolution in vivo. We have found evidence for parallel subclonal evolution, resulting in the same gene or signal transduction pathway being subject to distinct inactivating or activating somatic events in different regions of the same tumour (Gerlinger NEJM 2012). These data suggest that in-depth analysis of tumour evolution may help define routes through which tumours must progress, offering opportunities for novel therapeutic approaches. We will develop new animal models of ITH, by developing knock-out strains for two suppressors of replication stress and CIN, recently identified in our laboratory (Burrell Nature 2013). These models will be used to study cancer evolution in order to decipher the impact of selection pressures, such as DNA damaging agents and cancer cytotoxics, on genomic complexity and diversity in emergent resistant subclones. In addition, through combined cancer informatics and functional genomics approaches we aim to identify novel mechanisms driving tumour heterogeneity and biological processes that permit the propagation of heterogeneous cells using novel transposon based approaches. Developments in this proposal may lead to new insight into the two forces underpinning cancer evolution and therapeutic failure, diversity and selection

Appel à propositions

ERC-2013-CoG
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Régime de financement

ERC-CG - ERC Consolidator Grants

Institution d’accueil

THE FRANCIS CRICK INSTITUTE LIMITED
Contribution de l’UE
€ 1 145 438,30
Adresse
1 MIDLAND ROAD
NW1 1AT London
Royaume-Uni

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Région
London Inner London — West Camden and City of London
Type d’activité
Research Organisations
Contact administratif
Stéphane Maikovsky (Mr.)
Chercheur principal
Robert Charles Swanton (Dr.)
Liens
Coût total
Aucune donnée

Bénéficiaires (3)