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

Area of Science:

• Cell biology
• Molecular signaling
• Computational biology

Background:

• CD95 (also known as Fas/APO-1) is a death receptor involved in apoptosis and NF-κB activation.
• Cellular responses to CD95 stimulation exhibit significant heterogeneity.
• Understanding the mechanisms governing cell life/death decisions is crucial.

Purpose of the Study:

• To investigate how cells decide between life and death upon CD95 stimulation.
• To elucidate the roles of extrinsic and intrinsic noise in CD95 signaling pathways.
• To identify novel cellular responses to CD95 activation.

Main Methods:

• Development of a computational model for CD95 signaling.
• Imaging flow cytometry analysis of CD95 signaling pathways.
• Analysis of cell-to-cell variability in death-inducing complex (DISC) formation and NF-κB pathway gene expression.

Main Results:

• CD95 stimulation simultaneously activates caspase and NF-κB pathways within single cells.
• Cell fate is determined by the interplay between DISC formation variability (extrinsic noise) and NF-κB stochastic gene expression (intrinsic noise).
• A novel 'ambivalent' cellular response to CD95 stimulation was identified, where cells can either survive or undergo cell death.

Conclusions:

• The study reveals how competing apoptotic and anti-apoptotic pathways, modulated by noise, dictate cell fate.
• The findings highlight the existence of an ambivalent response state in CD95 signaling.
• This research provides insights into cell fate determination, relevant for developing anti-cancer therapies.