Mathematical Modelling of Cell-Fate Decision in Response to Death Receptor Engagement

Cytokines such as TNF and FASL can trigger death or survival depending on cell lines and cellular conditions. The mechanistic details of how a cell chooses among these cell fates are still unclear. The understanding of these processes is important since they are altered in many diseases, including cancer and AIDS. Using a discrete modelling formalism, we present a mathematical model of cell fate decision recapitulating and integrating the most consistent facts extracted from the literature. This model provides a generic high-level view of the interplays between NFκB pro-survival pathway, RIP1-dependent necrosis, and the apoptosis pathway in response to death receptor-mediated signals. Wild type simulations demonstrate robust segregation of cellular responses to receptor engagement. Model simulations recapitulate documented phenotypes of protein knockdowns and enable the prediction of the effects of novel knockdowns. In silico experiments simulate the outcomes following ligand removal at different stages, and suggest experimental approaches to further validate and specialise the model for particular cell types. We also propose a reduced conceptual model implementing the logic of the decision process. This analysis gives specific predictions regarding cross-talks between the three pathways, as well as the transient role of RIP1 protein in necrosis, and confirms the phenotypes of novel perturbations. Our wild type and mutant simulations provide novel insights to restore apoptosis in defective cells. The model analysis expands our understanding of how cell fate decision is made. Moreover, our current model can be used to assess contradictory or controversial data from the literature. Ultimately, it constitutes a valuable reasoning tool to delineate novel experiments.Author Summary: Activation of death receptors (TNFR and Fas) can trigger either survival or cell death according to the cell type and the cellular conditions. In other words, the same signal can have antagonist responses. On one hand, the cell can survive by activating the NFκB signalling pathway. On the other hand, it can die by apoptosis or necrosis. Apoptosis is a suicide mechanism, i.e., an orchestrated way to disrupt cellular components and pack them into specialized vesicles that can be easily removed from the environment, whereas necrosis is a type of death that involves release of intracellular components in the surrounding tissues, possibly causing inflammatory response and severe injury. We, biologists and theoreticians, have recapitulated and integrated known biological data from the literature into an influence diagram describing the molecular events leading to each possible outcome. The diagram has been translated into a dynamical Boolean model. Simulations of wild type, mutant cells and drug treatments qualitatively match current data, and predict several novel mutant phenotypes, along with general characteristics of the cell fate decision mechanism: transient activation of some key proteins in necrosis, mutual inhibitory cross-talks between the three pathways. Our model can further be used to assess contradictory data and address specific biological questions through in silico experiments.