Regulation of TRAIL-mediated apoptosis: Mechanisms and quantitative assessment of response heterogeneity at the cell population level

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The aim of this project is to better understand the induction of programmed cell death (apoptosis) in a clonally derived cell population. Apoptosis inducer is the molecule TRAIL (TNF-related apoptosis inducing ligand), a member of the TNF (tumor necrosis factor) superfamily, acting via stimulation of its respective membrane expressed death receptors. TRAIL is one of the most promising molecules currently tested in clinical studies as an antitumoral agent. We will experimentally1) investigate whether the heterogeneity in the apoptotic response of a cell population upon TRAIL stimulation is linked to the cell cycle status of individual tumor cells,2) determine in details the role of the intrinsic (mitochondrial) signaling pathway of apoptosis induction in our model cell line NCI-H460 with the focus on the regulatory network comprising the molecules Smac/DIABLO, XIAP and the caspases 9 and 3,3) and thereby provide comprehensive quantitative data and kinetics for establishing a predictive mathematical model of TRAIL-mediated apoptosis covering both single as well as the cell population responses.Importantly this experimental project is part of an interdisciplinary cooperation project with systems scientist from the Institute for Systems Theory and Automatic Control, University of Stuttgart. Although the experimental work described here can stand on its own and important scientific results are expected, a special surplus value is expected from this particular cooperation. Based on these experimental data produced by us the systems scientists will construct, analyze and verify a mathematical model describing a proliferating NCI-H460 cell population where TRAIL treatment induces apoptosis in most, but not all cells. Especially at later stages of this cooperation project (year three) model-derived predictions will support experimental work via optimization of experimental design and predictions regarding molecular key components and their behavior. We therefore expect high synergy effects between the experimental and the theoretical scientists in terms of an iterative process running in many cycles through both groups.