Fractional killing arises from cell‐to‐cell variability in overcoming a caspase activity threshold
Abstract When cells are exposed to death ligands such as TRAIL, a fraction undergoes apoptosis and a fraction survives; if surviving cells are re‐exposed to TRAIL, fractional killing is once again observed. Therapeutic antibodies directed against TRAIL receptors also cause fractional killing, even a...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Springer Nature
2015-05-01
|
| Series: | Molecular Systems Biology |
| Subjects: | |
| Online Access: | https://doi.org/10.15252/msb.20145584 |
| _version_ | 1797225421010370560 |
|---|---|
| author | Jérémie Roux Marc Hafner Samuel Bandara Joshua J Sims Hannah Hudson Diana Chai Peter K Sorger |
| author_facet | Jérémie Roux Marc Hafner Samuel Bandara Joshua J Sims Hannah Hudson Diana Chai Peter K Sorger |
| author_sort | Jérémie Roux |
| collection | DOAJ |
| description | Abstract When cells are exposed to death ligands such as TRAIL, a fraction undergoes apoptosis and a fraction survives; if surviving cells are re‐exposed to TRAIL, fractional killing is once again observed. Therapeutic antibodies directed against TRAIL receptors also cause fractional killing, even at saturating concentrations, limiting their effectiveness. Fractional killing arises from cell‐to‐cell fluctuations in protein levels (extrinsic noise), but how this results in a clean bifurcation between life and death remains unclear. In this paper, we identify a threshold in the rate and timing of initiator caspase activation that distinguishes cells that live from those that die; by mapping this threshold, we can predict fractional killing of cells exposed to natural and synthetic agonists alone or in combination with sensitizing drugs such as bortezomib. A phenomenological model of the threshold also quantifies the contributions of two resistance genes (c‐FLIP and Bcl‐2), providing new insight into the control of cell fate by opposing pro‐death and pro‐survival proteins and suggesting new criteria for evaluating the efficacy of therapeutic TRAIL receptor agonists. |
| first_indexed | 2024-03-13T03:10:50Z |
| format | Article |
| id | doaj.art-6e360956b93c4ce48e060381bc9b5364 |
| institution | Directory Open Access Journal |
| issn | 1744-4292 |
| language | English |
| last_indexed | 2024-04-24T14:08:44Z |
| publishDate | 2015-05-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | Molecular Systems Biology |
| spelling | doaj.art-6e360956b93c4ce48e060381bc9b53642024-04-03T09:41:47ZengSpringer NatureMolecular Systems Biology1744-42922015-05-01115n/an/a10.15252/msb.20145584Fractional killing arises from cell‐to‐cell variability in overcoming a caspase activity thresholdJérémie Roux0Marc Hafner1Samuel Bandara2Joshua J Sims3Hannah Hudson4Diana Chai5Peter K Sorger6Department of Systems Biology Harvard Medical School Boston MA USADepartment of Systems Biology Harvard Medical School Boston MA USADepartment of Systems Biology Harvard Medical School Boston MA USADepartment of Systems Biology Harvard Medical School Boston MA USAMerrimack Pharmaceuticals Cambridge MA USAMerrimack Pharmaceuticals Cambridge MA USADepartment of Systems Biology Harvard Medical School Boston MA USAAbstract When cells are exposed to death ligands such as TRAIL, a fraction undergoes apoptosis and a fraction survives; if surviving cells are re‐exposed to TRAIL, fractional killing is once again observed. Therapeutic antibodies directed against TRAIL receptors also cause fractional killing, even at saturating concentrations, limiting their effectiveness. Fractional killing arises from cell‐to‐cell fluctuations in protein levels (extrinsic noise), but how this results in a clean bifurcation between life and death remains unclear. In this paper, we identify a threshold in the rate and timing of initiator caspase activation that distinguishes cells that live from those that die; by mapping this threshold, we can predict fractional killing of cells exposed to natural and synthetic agonists alone or in combination with sensitizing drugs such as bortezomib. A phenomenological model of the threshold also quantifies the contributions of two resistance genes (c‐FLIP and Bcl‐2), providing new insight into the control of cell fate by opposing pro‐death and pro‐survival proteins and suggesting new criteria for evaluating the efficacy of therapeutic TRAIL receptor agonists.https://doi.org/10.15252/msb.20145584anti‐cancer therapeutic antibodiesapoptosisDR4, DR5 receptorsprogrammed cell deathTRAIL |
| spellingShingle | Jérémie Roux Marc Hafner Samuel Bandara Joshua J Sims Hannah Hudson Diana Chai Peter K Sorger Fractional killing arises from cell‐to‐cell variability in overcoming a caspase activity threshold Molecular Systems Biology anti‐cancer therapeutic antibodies apoptosis DR4, DR5 receptors programmed cell death TRAIL |
| title | Fractional killing arises from cell‐to‐cell variability in overcoming a caspase activity threshold |
| title_full | Fractional killing arises from cell‐to‐cell variability in overcoming a caspase activity threshold |
| title_fullStr | Fractional killing arises from cell‐to‐cell variability in overcoming a caspase activity threshold |
| title_full_unstemmed | Fractional killing arises from cell‐to‐cell variability in overcoming a caspase activity threshold |
| title_short | Fractional killing arises from cell‐to‐cell variability in overcoming a caspase activity threshold |
| title_sort | fractional killing arises from cell to cell variability in overcoming a caspase activity threshold |
| topic | anti‐cancer therapeutic antibodies apoptosis DR4, DR5 receptors programmed cell death TRAIL |
| url | https://doi.org/10.15252/msb.20145584 |
| work_keys_str_mv | AT jeremieroux fractionalkillingarisesfromcelltocellvariabilityinovercomingacaspaseactivitythreshold AT marchafner fractionalkillingarisesfromcelltocellvariabilityinovercomingacaspaseactivitythreshold AT samuelbandara fractionalkillingarisesfromcelltocellvariabilityinovercomingacaspaseactivitythreshold AT joshuajsims fractionalkillingarisesfromcelltocellvariabilityinovercomingacaspaseactivitythreshold AT hannahhudson fractionalkillingarisesfromcelltocellvariabilityinovercomingacaspaseactivitythreshold AT dianachai fractionalkillingarisesfromcelltocellvariabilityinovercomingacaspaseactivitythreshold AT peterksorger fractionalkillingarisesfromcelltocellvariabilityinovercomingacaspaseactivitythreshold |