Abstract B1-29: The effect of higher-order receptor clusters on TRAIL induced apoptotic signaling

Abstract

Abstract The trimeric TNF-related apoptosis-inducing ligand (TRAIL) is an endogenous ligand that binds to trimeric death receptors (DR4/5). TRAIL is known to induce apoptosis mainly in malignant cells while normal cells remain unaffected. This makes TRAIL a most interesting target for cancer therapy. We investigate the effects of ligand valency on the degree of Caspase-8 activation and apoptosis induction. As a model system we use the semi-sensitive cell line DU145 and multivalent anti-DR5 fibronectin domains that can potentially form higher-order receptor clusters. In order to disentangle the effects of receptor clusters of different size, a dynamic model of ligand-receptor binding and Caspase-8 activation is coupled to a model of cell growth and cell death. The dynamic model is calibrated using quantitative experimental data of ligand on cell binding, Caspase-8 activity and cell viability. Our results show that higher-order receptor clusters do amplify apoptotic signaling. The model predicts that receptor clusters of size three and six are more abundant than others, indicating the special role of preformed receptor trimers. However, Caspase-8 activation only increases after receptor clusters of size larger than three. On the cell population level, the model can quantitatively predict the induction of apoptosis in this cell line. This work is an important step towards an integrative model of TRAIL induced apoptosis that finally aims at the understanding of heterogeneity both on a single cell level across cell lines. Citation Format: Andreas Raue, Diana Chai, Hannah Hudson, Eric Tam, Birgit Schoeberl. The effect of higher-order receptor clusters on TRAIL induced apoptotic signaling. [abstract]. In: Proceedings of the AACR Special Conference on Computational and Systems Biology of Cancer; Feb 8-11 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 2):Abstract nr B1-29.