Combining lineage correlations and a small molecule inhibitor to detect circadian control of the cell cycle.

Abstract

Chronotherapy has emerged as an exciting possibility for improving treatment regimens in cancer. A strong influence of the circadian clock on the cell cycle is a crucial requirement for successful chronotherapy. However, though a number of molecular interactions have been discovered between these two oscillators, it remains unclear whether these interactions are sufficient to generate emergent control of cellular proliferation. In this work, we computationally explore a strategy to detect clock control over the cell cycle, by computing lineage correlations in cell cycle times in the presence and absence of the clock inhibitor KL001. Using phenomenological models, we and others have previously suggested that the cousin-mother inequality - a phenomenon where cousin cells show stronger cell cycle time correlations than mother-daughter pairs, could be leveraged to probe circadian effects on cellular proliferation. Using stochastic simulations calibrated to match HCT116 colon cancer proliferation datasets, we demonstrate that the established gene-networks giving rise to the cell cycle and circadian oscillations are sufficient to generate the cousin-mother inequality. In the presence of KL001 which stabilizes CRY1, our models predict greater than 50% decrease in the cousin-mother inequality, but counter-intuitively, very little change in population growth rates. Our results predict a range of underlying cell cycle times where the cousin-mother inequality should be observed, and consequently suggest the exciting possibility of combining measurements of lineage correlations with KL001 as a probe of circadian clock - cell cycle interactions.