Quantitative single cell analysis uncovers the life/death decision in CD95 network

PLoS Comput Biol. 2018 Sep 26;14(9):e1006368. doi: 10.1371/journal.pcbi.1006368. eCollection 2018 Sep.

Abstract

CD95/Fas/APO-1 is a member of the death receptor family that triggers apoptotic and anti-apoptotic responses in particular, NF-κB. These responses are characterized by a strong heterogeneity within a population of cells. To determine how the cell decides between life and death we developed a computational model supported by imaging flow cytometry analysis of CD95 signaling. Here we show that CD95 stimulation leads to the induction of caspase and NF-κB pathways simultaneously in one cell. The related life/death decision strictly depends on cell-to-cell variability in the formation of the death-inducing complex (DISC) on one side (extrinsic noise) vs. stochastic gene expression of the NF-κB pathway on the other side (intrinsic noise). Moreover, our analysis has uncovered that the stochasticity in apoptosis and NF-kB pathways leads not only to survival or death of a cell, but also causes a third type of response to CD95 stimulation that we termed ambivalent response. Cells in the ambivalent state can undergo cell death or survive which was subsequently validated by experiments. Taken together, we have uncovered how these two competing pathways control the fate of a cell, which in turn plays an important role for development of anti-cancer therapies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis
  • Caspase 3 / metabolism
  • Caspases / metabolism
  • Cell Lineage
  • Computer Simulation
  • Flow Cytometry
  • HeLa Cells
  • Humans
  • Models, Theoretical
  • NF-kappa B / metabolism
  • Signal Transduction
  • Single-Cell Analysis / methods*
  • fas Receptor / physiology*

Substances

  • NF-kappa B
  • fas Receptor
  • Caspase 3
  • Caspases

Grants and funding

We acknowledge BMBF (eBIO project “ImmunoQuant” - TPU - 0316170G), (eBIO project “AML” 031A304), the center of dynamic systems (CDS), funded by the EU-programme ERDF (European Regional Development Fund), DFG (LA 2386/6-1) and RSF (Russian Science Foundation) 14-44-00011 for supporting our work. CD95 network for model topology was constructed with the support of the Russian Science Foundation grant “Programmed cell death induced via death receptors: Delineating molecular mechanisms of apoptosis initiation via molecular modeling” 14-44-00011. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.