Core Models of Receptor Reactions to Evaluate Basic Pathway Designs Enabling Heterogeneous Commitments to Apoptosis

Abstract

Isogenic cells can respond differently to cytotoxic drugs, such as the tumor necrosis factor-related apoptosis inducing ligand (TRAIL), with only a fraction committing to apoptosis. Since non-genetic transient resistance to TRAIL has been shown to dependent on caspase-8 dynamics at the receptor level in vitro, here we investigate the core reactions leading to caspase-8 activation, based on mass-action kinetics models, to evaluate the basic mechanisms giving rise to the observed heterogeneous response. In this work, we fit our models to single-cell trajectories of time-resolved caspase-8 activation measured in clonal cells after treatment with TRAIL. Then, we analyse our results to assess the relevance of each model and evaluate how well it captures the extent of biological heterogeneity observed in vitro. Particularly, we focus on a positive feedback loop on caspase-8, the impacts of initial condition variations and the relevance of the caspase-8 degradation.

Two-level modeling approach to identify the regulatory dynamics capturing drug response heterogeneity in single-cells

“…But the experiments also suggest a cooperative and hierarchical binding of caspase-8 and cFLIP to reveal a similar cooperative binding effect between caspase-8 and caspase-10, since binding of caspase-10 is ineffective in the absence of caspase-8. To further test this relationship between caspases-8 and -10, we developed a more detailed model in 45 , where caspase-10 acts as an intermediary regulatory protein and sets the threshold for the maximal slope of caspase-8 activation.…”

Estimation Algorithm for a Hybrid PDE–ODE Model Inspired by Immunocompetent Cancer-on-Chip Experiment

“…Hybrid models, developed including the macroscopic and microscopic scales, have been deeply studied in recent years, see [41][42][43][44]. In particular, in [41] a hybrid discretecontinuous model of metastatic cancer cell migration was developed, while in [45] a hybrid discrete-continuum approach was applied to model Turing pattern formation. In [43] a 3D agent-based model is proposed using an off-lattice approach to simulate vasculogenesis.…”