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Modeling cell response heterogeneity to pro-apoptotic ligands

Luis Carlos Gomes Pereira 1, 2
1 BIOCORE - Biological control of artificial ecosystems
CRISAM - Inria Sophia Antipolis - Méditerranée , LOV - Laboratoire d'océanographie de Villefranche, INRAE - Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement
Abstract : Apoptosis is an essential physiological process through which organisms are able to equilibrate their cell numbers and maintain tissues in healthy and functional conditions. Despite the recent advances in the field, little is known on the molecular mechanisms controlling individual cell decisions to either engage or avoid the activation of this pathway upon cancer treatment, which inevitably impacts on therapeutics development. To obtain a global view of the intervening proteins and their role on cell response dynamics to anticancer drugs, a new and detailed description of the apoptosis pathway at the receptor level was translated into a system of ordinary differential equations. The model was calibrated to single-cell data, from recent experiments on a population of HeLa cells exhibiting a highly heterogeneous response when exposed to the death-inducing ligand TRAIL. The sensitivities of the apoptotic reactions in our model were evaluated using the diversity of experimental behaviors observed in vitro. A series of computational tests and analyses were performed with our model to identify the origins of cell response heterogeneity. New features of the apoptotic pathway emerged from a comparison of different heterogeneity modeling approaches, detecting a set of key reactions to be further expanded. These analyses yield new biological insights and highlights the importance of refining regulation of death receptor complex activity, possibly through Caspase-10 as suggested from new experimental discoveries. This thesis offers a novel framework that can be used to uncover important biological insights using single-cell data of heterogeneous dynamical pathways.
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Luis Carlos Gomes Pereira. Modeling cell response heterogeneity to pro-apoptotic ligands. Automatic Control Engineering. COMUE Université Côte d'Azur (2015 - 2019), 2019. English. ⟨NNT : 2019AZUR4081⟩. ⟨tel-02865212⟩

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