Investigating how dormant senescent cells can drive drug-resistance following chemotherapy

Most anti-cancer chemotherapeutics work by inducing DNA damage and arresting the cell cycle in either G1 or G2 phase. A frequent outcome of this arrest is that cells exit the cell cycle into a state known as senescence. Remarkably, senescent cells that originated from a G1 or G2 arrested have never previously been compared, even though these states are very different.

The first goal of this studentship will be to characterise these different states using mass-spec proteomics and RNA sequencing. This is important because it has become clear recently that senescent cells can lay dormant in tumours following chemotherapy, before later re-entering the cell cycle and causing drug resistance. How and why dormant cells can cause drug resistance is unknown. We hypothesise that dormant cells that became senescent from G1 or G2 phases will behave very differently when they re-enter the cell cycle. That is because G2 arrested cells have doubled their genome and centrosome numbers, both of which are known to drive genome instability and cancer. Therefore, dormant G2 cells are likely to be much more dangerous if they re-enter the cell cycle, in particular, they will exhibit genomic instability which is known to drive drug resistance.

The second goal of the studentship is to test this hypothesis by characterising cell cycle re-entry in senescent cells using a range of fixed and live cell microscopy techniques, before linking any defects to chromosomal instability, tumour evolution and drug resistance.

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