Individual cells choose between alternative states in many aspects of biology. My dissertation seeks to understand the kinetics and mechanism by which cancer cells decide between the state of death and survival during mitosis, in particular the prolonged mitotic arrest induced by anti-mitotic drugs. Cell fates are dictated by two alternative pathways during prolonged mitosis, one that promotes slippage out of mitosis and cell survival, the other that promotes cell death. In the first part of the dissertation, I aim to describe the pathway that triggers mitotic cell death in molecular terms. Understanding the molecular components of this pathway is important not only from a basic science perspective, but also from a cancer therapeutic perspective, as it helps to broaden our spectra of molecular targets that would potentially drive the overall cellular decisions towards more cell death, in the context of anti-mitotic drugs that work by killing dividing cells. I also explore variation between cancer cell lines in decision-making towards death versus slippage and survival. In the second part of the dissertation, I aim to quantify the decision-making process, and the variation of it, in terms of overall pathway dynamics rather than molecular details, and present evidence that variability in cell-to-cell behavior is attributed to the stochastic kinetic competition between two mechanistically independent pathways that controls death and mitotic slippage respectively.
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