Abstract SY17-03: Inferring cell death networks from biochemical data
Peter Karl Sorger, Sabrina L. Spencer, Suzanne Gaudet, Bree B. Aldridge, Deborah A. Flusberg, John A. Bachman, Josh Sims · Cancer Research · 2011
Abstract The responses of cells to extracellular ligands results in a series of complex spatiotemporal changes in protein levels and state that vary considerably from one cell to the next. I will discuss our attempts to understand the biochemical mechanisms underlying these phenomena with a focus on TRAIL and Fas ligand in human tumor cells. These molecules are prototypical inducers of receptor-mediated (extrinsic) apoptosis and TRAIL is a first-in-class investigational therapeutic. I will discuss the development and application of computational methods for constructing, managing, calibrating and validating detailed kinetic models of core apoptotic process. With these methods we aim to go beyond the informal pictorial models that currently dominating molecular biology and create probabilistic mathematical constructs that assign rigorous “degrees of belief” to specific biochemical hypothesis given prior knowledge and a specific set of empirical data. I will discuss why some TRAIL-treated human cells die within ∼40 min, some only after 12 hr and yet others live indefinitely. We have explored three explanations for these differences: (i) genetic or epigenetic variation (ii) the involvement of one or more biochemical processes subject to stochastic fluctuation (iii) transient but deterministic differences in cell state. I will illustrate how all three interact on different time scales to determine those aspects of cellular physiology that are highly invariant and those that are variable and I will present a modeling framework for understanding the impact of specific protein factors in cell-to-cell variability. A key conclusion from this work is that variability in the responses of cells to drugs is inherent to the stochastic operation of the biochemical pathways that anti-cancer drugs target. Fractional killing is one inevitable consequence. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr SY17-03. doi:10.1158/1538-7445.AM2011-SY17-03