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TRAIL-induced variation of cell signaling states provides nonheritable resistance to apoptosis

TNFα-related apoptosis-inducing ligand (TRAIL), specifically initiates programmed cell death, but often fails to eradicate all cells, making it an ineffective therapy for cancer. This fractional killing is linked to cellular variation that bulk assays cannot capture. Here, we quantify the diversity...

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Autores principales: Baskar, Reema, Fienberg, Harris G, Khair, Zumana, Favaro, Patricia, Kimmey, Sam, Green, Douglas R, Nolan, Garry P, Plevritis, Sylvia, Bendall, Sean C
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Life Science Alliance LLC 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6848270/
https://www.ncbi.nlm.nih.gov/pubmed/31704709
http://dx.doi.org/10.26508/lsa.201900554
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author Baskar, Reema
Fienberg, Harris G
Khair, Zumana
Favaro, Patricia
Kimmey, Sam
Green, Douglas R
Nolan, Garry P
Plevritis, Sylvia
Bendall, Sean C
author_facet Baskar, Reema
Fienberg, Harris G
Khair, Zumana
Favaro, Patricia
Kimmey, Sam
Green, Douglas R
Nolan, Garry P
Plevritis, Sylvia
Bendall, Sean C
author_sort Baskar, Reema
collection PubMed
description TNFα-related apoptosis-inducing ligand (TRAIL), specifically initiates programmed cell death, but often fails to eradicate all cells, making it an ineffective therapy for cancer. This fractional killing is linked to cellular variation that bulk assays cannot capture. Here, we quantify the diversity in cellular signaling responses to TRAIL, linking it to apoptotic frequency across numerous cell systems with single-cell mass cytometry (CyTOF). Although all cells respond to TRAIL, a variable fraction persists without apoptotic progression. This cell-specific behavior is nonheritable where both the TRAIL-induced signaling responses and frequency of apoptotic resistance remain unaffected by prior exposure. The diversity of signaling states upon exposure is correlated to TRAIL resistance. Concomitantly, constricting the variation in signaling response with kinase inhibitors proportionally decreases TRAIL resistance. Simultaneously, TRAIL-induced de novo translation in resistant cells, when blocked by cycloheximide, abrogated all TRAIL resistance. This work highlights how cell signaling diversity, and subsequent translation response, relates to nonheritable fractional escape from TRAIL-induced apoptosis. This refined view of TRAIL resistance provides new avenues to study death ligands in general.
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spelling pubmed-68482702019-11-21 TRAIL-induced variation of cell signaling states provides nonheritable resistance to apoptosis Baskar, Reema Fienberg, Harris G Khair, Zumana Favaro, Patricia Kimmey, Sam Green, Douglas R Nolan, Garry P Plevritis, Sylvia Bendall, Sean C Life Sci Alliance Research Articles TNFα-related apoptosis-inducing ligand (TRAIL), specifically initiates programmed cell death, but often fails to eradicate all cells, making it an ineffective therapy for cancer. This fractional killing is linked to cellular variation that bulk assays cannot capture. Here, we quantify the diversity in cellular signaling responses to TRAIL, linking it to apoptotic frequency across numerous cell systems with single-cell mass cytometry (CyTOF). Although all cells respond to TRAIL, a variable fraction persists without apoptotic progression. This cell-specific behavior is nonheritable where both the TRAIL-induced signaling responses and frequency of apoptotic resistance remain unaffected by prior exposure. The diversity of signaling states upon exposure is correlated to TRAIL resistance. Concomitantly, constricting the variation in signaling response with kinase inhibitors proportionally decreases TRAIL resistance. Simultaneously, TRAIL-induced de novo translation in resistant cells, when blocked by cycloheximide, abrogated all TRAIL resistance. This work highlights how cell signaling diversity, and subsequent translation response, relates to nonheritable fractional escape from TRAIL-induced apoptosis. This refined view of TRAIL resistance provides new avenues to study death ligands in general. Life Science Alliance LLC 2019-11-08 /pmc/articles/PMC6848270/ /pubmed/31704709 http://dx.doi.org/10.26508/lsa.201900554 Text en © 2019 Baskar et al. https://creativecommons.org/licenses/by/4.0/This article is available under a Creative Commons License (Attribution 4.0 International, as described at https://creativecommons.org/licenses/by/4.0/).
spellingShingle Research Articles
Baskar, Reema
Fienberg, Harris G
Khair, Zumana
Favaro, Patricia
Kimmey, Sam
Green, Douglas R
Nolan, Garry P
Plevritis, Sylvia
Bendall, Sean C
TRAIL-induced variation of cell signaling states provides nonheritable resistance to apoptosis
title TRAIL-induced variation of cell signaling states provides nonheritable resistance to apoptosis
title_full TRAIL-induced variation of cell signaling states provides nonheritable resistance to apoptosis
title_fullStr TRAIL-induced variation of cell signaling states provides nonheritable resistance to apoptosis
title_full_unstemmed TRAIL-induced variation of cell signaling states provides nonheritable resistance to apoptosis
title_short TRAIL-induced variation of cell signaling states provides nonheritable resistance to apoptosis
title_sort trail-induced variation of cell signaling states provides nonheritable resistance to apoptosis
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6848270/
https://www.ncbi.nlm.nih.gov/pubmed/31704709
http://dx.doi.org/10.26508/lsa.201900554
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