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THESEUS Report Summary

Project ID: 617844
Funded under: FP7-IDEAS-ERC
Country: United Kingdom

Mid-Term Report Summary - THESEUS (Tumour Heterogeneity and Somatic Evolution of Unstable cancer genomes)

Analysis of cancers has revealed evidence for diversifying genetic evolution and intratumour heterogeneity (ITH) within cell populations. While there is a growing body of evidence investigating the extent of ITH and how it changes during cancer progression, insights into the mechanisms of genetic instability accounting for ITH and its tolerance or the processes driving the dynamic changes in the cancer cell populations remain limited. This project aims to identify how cell to cell heterogeneity is generated and sustained in cancer populations, and importantly, to use this knowledge to develop improved animal models of ITH that more faithfully recapitulate cancer evolution in a human, in order to study the evolutionary forces driving cancer dynamics during disease progression.

So far, we have generated novel animal lines that exhibit similar patterns of genetic instability observed in cancers, which will be used to study the roles of DNA replication stress and pre-mitotic chromosome segregation errors driving cell to cell variation in colorectal cancer. We are also characterising lung cancer evolutionary dynamics in animal models, tracking cancer cell populations as the disease progress through therapy in a highly controlled manner. We have also used multiple different genetic and biochemical assays to identify and characterise genes that govern the initiation, maintenance and tolerance of chromosomal instability in cells. In three studies that we have published, we have shown that dysfunction in genes controlling cellular processes such as mitotic timing and cell death, can alter a cell’s ability to tolerate genetic instability. These studies have shed light on both p53 dependent and p53 independent routes to the tolerance of chromosomal instability.

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United Kingdom
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