Jamie Dean

Radiotherapy is used in the treatment of approximately half of patients with cancer. Resistance to radiotherapy can occur through a subpopulation of cells transiently entering a cell cycle-arrested state, during which they are able to tolerate the treatment, which predominantly targets rapidly proliferating cells. These surviving cells can then re-enter a proliferative state to repopulate the tumour. To design new therapeutic strategies to overcome this resistance mechanism, an improved understanding of cell cycle regulation in response to radiotherapy is needed. Towards generating this knowledge, we investigated regulation of the cell cycle arrest gene p21 by the transcription factor p53, through integrating single cell timelapse fluorescence microscopy and stochastic modelling. We determined that p21 transcription is governed by an incoherent feedforward loop mediated by MDM2. This network architecture facilitates rapid induction of p21 expression and variability in p21 transcription, potentially contributing to treatment resistance. We are also trying to understand mechanisms of inheritance of the rate of cell cycle progression and sensitivity to radiotherapy. To do so we are developing a computational tool to fit and compare a range of mathematical models, describing different proposed mechanisms of cellular inheritance (e.g. circadian gating of the cell cycle with inheritance of the clock phase), to cell lineage trees extracted from timelapse microscopy data. Distinguishing between these alternative mechanisms will guide the development of novel therapeutic strategies (e.g. chronotherapy) in the future.