Modulating cell-to-cell variability and sensitivity to death ligands by co-drugging
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Updated: May 10, 2026
Quantification of Cytokine-Induced Cell Death in Human Colonic Organoids Using Live Fluorescence Microscopy
Published on: August 2, 2024
Deborah A Flusberg1, Peter K Sorger
1Center for Cell Decision Processes, Department of Systems Biology, Harvard Medical School, 200 Longwood Ave, Boston, MA 02115, USA.
Abstract:
TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) holds promise as an anti-cancer therapeutic but efficiently induces apoptosis in only a subset of tumor cell lines. Moreover, even in clonal populations of responsive lines, only a fraction of cells dies in response to TRAIL and individual cells exhibit cell-to-cell variability in the timing of cell death. Fractional killing in these cell populations appears to arise not from genetic differences among cells but rather from differences in gene expression states, fluctuations in protein levels and the extent to which TRAIL-induced death or survival pathways become activated. In this study, we ask how cell-to-cell variability manifests in cell types with different sensitivities to TRAIL, as well as how it changes when cells are exposed to combinations of drugs. We show that individual cells that survive treatment with TRAIL can regenerate the sensitivity and death-time distribution of the parental population, demonstrating that fractional killing is a stable property of cell populations. We also show that cell-to-cell variability in the timing and probability of apoptosis in response to treatment can be tuned using combinations of drugs that together increase apoptotic sensitivity compared to treatment with one drug alone. In the case of TRAIL, modulation of cell-to-cell variability by co-drugging appears to involve a reduction in the threshold for mitochondrial outer membrane permeabilization.
Insights
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) shows variable anti-cancer effects due to cell-to-cell differences. Combining drugs can tune this variability and enhance apoptosis, offering a promising therapeutic strategy.
Area of Science:
- Cancer Biology
- Cellular Signaling
- Pharmacology
Background:
- Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising anti-cancer agent, but its efficacy is limited by variable apoptosis induction across tumor cell lines.
- Fractional cell killing by TRAIL, even in clonal populations, is attributed to cell-to-cell variability in gene expression and protein levels, not genetic differences.
- Understanding and modulating this cell-to-cell variability is crucial for optimizing TRAIL-based cancer therapies.
Purpose of the Study:
- To investigate how cell-to-cell variability in TRAIL-induced apoptosis differs across cell types with varying sensitivities.
- To explore how drug combinations affect cell-to-cell variability in apoptosis timing and probability.
- To elucidate the mechanisms underlying the modulation of TRAIL-induced apoptosis by co-drugging.
Main Methods:
- Analysis of cell-to-cell variability in apoptosis induction by TRAIL in different tumor cell lines.
- Assessment of TRAIL sensitivity and cell death timing in clonal populations after treatment.
- Evaluation of drug combinations for their impact on apoptotic sensitivity and cell-to-cell variability.
Main Results:
- Fractional killing by TRAIL is a stable property of cell populations, with surviving cells regenerating parental sensitivity distributions.
- Drug combinations can effectively tune cell-to-cell variability in apoptosis timing and probability, enhancing overall apoptotic sensitivity.
- Co-drugging with TRAIL appears to reduce the threshold for mitochondrial outer membrane permeabilization, a key step in apoptosis.
Conclusions:
- Cell-to-cell variability in TRAIL response is a fundamental characteristic that can be modulated by therapeutic interventions.
- Combination therapies offer a strategy to overcome the limitations of single-agent TRAIL therapy by enhancing and standardizing apoptosis induction.
- Targeting the mitochondrial pathway through drug combinations may be a key mechanism for improving anti-cancer drug efficacy.
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