Core Models of Receptor Reactions to Evaluate Basic Pathway Designs Enabling Heterogeneous Commitments to Apoptosis
Résumé
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.
Domaines
Sciences du Vivant [q-bio] Biologie cellulaire Biochimie, Biologie Moléculaire Cancer Ingénierie biomédicale Pharmacologie Systèmes dynamiques [math.DS] Intelligence artificielle [cs.AI] Bio-informatique [q-bio.QM] Biotechnologie Apprentissage [cs.LG] Modélisation et simulation Traitement des images [eess.IV] Traitement du signal et de l'image [eess.SP] Bio-Informatique, Biologie Systémique [q-bio.QM]
Origine : Fichiers produits par l'(les) auteur(s)