Non-genetic origins of cell-to-cell variability in TRAIL-induced apoptosis

By S. Spencer, S. Gaudet, J. Albeck, J. Burke, Peter K. Sorger. Nature, 2009

1,065 citations recorded by the source corpus.

In microorganisms, noise in gene expression gives rise to cell-to-cell variability in protein concentrations. In mammalian cells, protein levels also vary and individual cells differ widely in their responsiveness to uniform physiological stimuli. In the case of apoptosis mediated by TRAIL (tumour necrosis factor (TNF)-related apoptosis-inducing ligand) it is common for some cells in a clonal population to die while others survive—a striking divergence in cell fate. Among cells that die, the time between TRAIL exposure and caspase activation is highly variable. Here we image sister cells expressing reporters of caspase activation and mitochondrial outer membrane permeabilization after exposure to TRAIL. We show that naturally occurring differences in the levels or states of proteins regulating receptor-mediated apoptosis are the primary causes of cell-to-cell variability in the timing and probability of death in human cell lines. Protein state is transmitted from mother to daughter, giving rise to transient heritability in fate, but protein synthesis promotes rapid divergence so that sister cells soon become no more similar to each other than pairs of cells chosen at random. Our results have implications for understanding ‘fractional killing’ of tumour cells after exposure to chemotherapy, and for variability in mammalian signal transduction in general.

Subfields: Biophysics, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/f5c3b6c19b39829930c8ec30ed3247f915d712e8

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Biophysics

In Molecular Biology

Citations in the corpus

Caspases and their substrates (2017, methodology): “It is known that there is a significant time delay of a few hours prior to the induction of caspase activation in cells.(70,71) An extensive study of the transcriptional and translational events that precede induction of caspases in bortezomib-treated MM1S cells was conducted using RNAseq, ribosomal”
Tumor heterogeneity: causes and consequences (2009, background): “This heterogeneity does not depend on genetic or epigenetic mechanisms but is instead caused by apparently noise-driven differences in levels of protein expression [22].”
Caspase functions in cell death and disease. (2013, background): “Type I and II cells differ in their content of intracellular inhibitor of apoptosis proteins (IAPs), which block executioner caspase function unless suppressed by proteins released from the mitochondria (Jost et al. 2009; Spencer et al. 2009).”
Understanding MAPK Signaling Pathways in Apoptosis (2020, background): “Interestingly, it has been shown that cells present a heterogeneous composition in pro- and anti-apoptotic factors, which are the primary causes of cell-to-cell variability in the timing and probability of death in TRAIL (TNF-related apoptosis-inducing ligand)-induced apoptosis [153].”
The BCL-2 Family Reunion (2010, background): “Further evidence for bcl-2 and c-myc synergy in a double transgenic (Em-bcl-2/c-myc) model confirmed that bcl-2 contributes to lymphomagenesis by allowing a cell to survive despite c-myc expression (Strasser et al., 1990).”
An Integrated Mechanistic Model of Pan-Cancer Driver Pathways Predicts Stochastic Proliferation and Death (2017, background): “Intra-tumoral heterogeneity is genetic (Landau et al., 2013) and non-genetic (Spencer et al., 2009), so we require accounting for such noise.”
Cellular heterogeneity: when do differences make a difference? (2010, background): “…the difficult and fascinating problems of identifying the origins of cellular heterogeneity (Brock et al., 2009; Muotri et al., 2005; Raj and c. van Oudenaarden, 2008; Spencer et al., 2009), or understanding its differences in vivo and in vitro or in physiological and pathophysiological conditions.”
Cellular Decision-Making and Biological Noise: From Microbes to Mammals (2011, background): “In addition to cell differentiation, one of the most important processes recently shown to rely on cellular decision making is apoptosis (Spencer et al., 2009).”