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

Abstract

In microorganisms, noise in gene expression gives rise to cell-to-cell variability in protein concentrations1–7. In mammalian cells, protein levels also vary8–10 and individual cells differ widely in responsiveness to uniform physiological stimuli11–15. In the case of apoptosis mediated by TRAIL (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 permeabilisation (MOMP) following 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. 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 tumor cells following exposure to chemotherapy, and for variability in mammalian signal transduction in general.

TRAIL-transduced multipotent mesenchymal stromal cells (TRAIL-MSC) overcome TRAIL resistance in selected CRC cell lines in vitro and in vivo

“…The relevance of such cell-to-cell variability for differential apoptosis induction by TRAIL has been described. 25 It remains speculative whether and which of these features are responsible for the observed differential response in our model.…”

Network‐based drugs and biomarkers

“…Cell behaviour and phenotype are directly controlled by dynamic networks of protein interactions in response to external or internal cues/stimuli (Figures 1, 2). Signalling networks, such as those regulated by kinases and phosphobinding domains (eg the SH2 domains) are essential for the integrative response a cell must make at any given point in time to extra-or intracellular cues [4][5][6][7][8][9][10][11].…”

“…In a similar study, the MIT labs showed how common information processing mediates cell-specific responses to stimuli [5]. Therefore, to fully understand a cellular response to a perturbation (such as to a drug), it is essential to analyse this in the context of the cell's multivariate state [5][6][7]. This observation does not just have implications for biomarker discovery, as discussed below, but also for how analysis of biological systems should be performed.…”

“…However, these efforts make assumptions that might conflict with our current understanding of how molecular networks and systems become disease driving. Cellular signalling networks are highly dynamic, in both structure and utilization [4] and in both cell-and tissue-specific contexts [5,6] ( Figure 1). …”

“…An essential aspect of cellular signalling networks is that at any given time they are in a given state that impacts directly on the cellular response to an environmental stimulation (or cue) [4][5][6][7][8]. This multivariate nature enables cells to respond to multiple input cues in an integrative and quantitative manner [7] (Figure 2).…”