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Ultrarapid lytic granule release from CTLs activates Ca(2+)-dependent synaptic resistance pathways in melanoma cells

Human cytotoxic T lymphocytes (CTLs) exhibit ultrarapid lytic granule secretion, but whether melanoma cells mobilize defense mechanisms with commensurate rapidity remains unknown. We used single-cell time-lapse microscopy to offer high spatiotemporal resolution analyses of subcellular events in mela...

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Autores principales: Filali, Liza, Puissegur, Marie-Pierre, Cortacero, Kevin, Cussat-Blanc, Sylvain, Khazen, Roxana, Van Acker, Nathalie, Frenois, François-Xavier, Abreu, Arnaud, Lamant, Laurence, Meyer, Nicolas, Vergier, Béatrice, Müller, Sabina, McKenzie, Brienne, Valitutti, Salvatore
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for the Advancement of Science 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8849291/
https://www.ncbi.nlm.nih.gov/pubmed/35171665
http://dx.doi.org/10.1126/sciadv.abk3234
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author Filali, Liza
Puissegur, Marie-Pierre
Cortacero, Kevin
Cussat-Blanc, Sylvain
Khazen, Roxana
Van Acker, Nathalie
Frenois, François-Xavier
Abreu, Arnaud
Lamant, Laurence
Meyer, Nicolas
Vergier, Béatrice
Müller, Sabina
McKenzie, Brienne
Valitutti, Salvatore
author_facet Filali, Liza
Puissegur, Marie-Pierre
Cortacero, Kevin
Cussat-Blanc, Sylvain
Khazen, Roxana
Van Acker, Nathalie
Frenois, François-Xavier
Abreu, Arnaud
Lamant, Laurence
Meyer, Nicolas
Vergier, Béatrice
Müller, Sabina
McKenzie, Brienne
Valitutti, Salvatore
author_sort Filali, Liza
collection PubMed
description Human cytotoxic T lymphocytes (CTLs) exhibit ultrarapid lytic granule secretion, but whether melanoma cells mobilize defense mechanisms with commensurate rapidity remains unknown. We used single-cell time-lapse microscopy to offer high spatiotemporal resolution analyses of subcellular events in melanoma cells upon CTL attack. Target cell perforation initiated an intracellular Ca(2+) wave that propagated outward from the synapse within milliseconds and triggered lysosomal mobilization to the synapse, facilitating membrane repair and conferring resistance to CTL induced cytotoxicity. Inhibition of Ca(2+) flux and silencing of synaptotagmin VII limited synaptic lysosomal exposure and enhanced cytotoxicity. Multiplexed immunohistochemistry of patient melanoma nodules combined with automated image analysis showed that melanoma cells facing CD8(+) CTLs in the tumor periphery or peritumoral area exhibited significant lysosomal enrichment. Our results identified synaptic Ca(2+) entry as the definitive trigger for lysosomal deployment to the synapse upon CTL attack and highlighted an unpredicted defensive topology of lysosome distribution in melanoma nodules.
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spelling pubmed-88492912022-03-04 Ultrarapid lytic granule release from CTLs activates Ca(2+)-dependent synaptic resistance pathways in melanoma cells Filali, Liza Puissegur, Marie-Pierre Cortacero, Kevin Cussat-Blanc, Sylvain Khazen, Roxana Van Acker, Nathalie Frenois, François-Xavier Abreu, Arnaud Lamant, Laurence Meyer, Nicolas Vergier, Béatrice Müller, Sabina McKenzie, Brienne Valitutti, Salvatore Sci Adv Biomedicine and Life Sciences Human cytotoxic T lymphocytes (CTLs) exhibit ultrarapid lytic granule secretion, but whether melanoma cells mobilize defense mechanisms with commensurate rapidity remains unknown. We used single-cell time-lapse microscopy to offer high spatiotemporal resolution analyses of subcellular events in melanoma cells upon CTL attack. Target cell perforation initiated an intracellular Ca(2+) wave that propagated outward from the synapse within milliseconds and triggered lysosomal mobilization to the synapse, facilitating membrane repair and conferring resistance to CTL induced cytotoxicity. Inhibition of Ca(2+) flux and silencing of synaptotagmin VII limited synaptic lysosomal exposure and enhanced cytotoxicity. Multiplexed immunohistochemistry of patient melanoma nodules combined with automated image analysis showed that melanoma cells facing CD8(+) CTLs in the tumor periphery or peritumoral area exhibited significant lysosomal enrichment. Our results identified synaptic Ca(2+) entry as the definitive trigger for lysosomal deployment to the synapse upon CTL attack and highlighted an unpredicted defensive topology of lysosome distribution in melanoma nodules. American Association for the Advancement of Science 2022-02-16 /pmc/articles/PMC8849291/ /pubmed/35171665 http://dx.doi.org/10.1126/sciadv.abk3234 Text en Copyright © 2022 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC). https://creativecommons.org/licenses/by-nc/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license (https://creativecommons.org/licenses/by-nc/4.0/) , which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.
spellingShingle Biomedicine and Life Sciences
Filali, Liza
Puissegur, Marie-Pierre
Cortacero, Kevin
Cussat-Blanc, Sylvain
Khazen, Roxana
Van Acker, Nathalie
Frenois, François-Xavier
Abreu, Arnaud
Lamant, Laurence
Meyer, Nicolas
Vergier, Béatrice
Müller, Sabina
McKenzie, Brienne
Valitutti, Salvatore
Ultrarapid lytic granule release from CTLs activates Ca(2+)-dependent synaptic resistance pathways in melanoma cells
title Ultrarapid lytic granule release from CTLs activates Ca(2+)-dependent synaptic resistance pathways in melanoma cells
title_full Ultrarapid lytic granule release from CTLs activates Ca(2+)-dependent synaptic resistance pathways in melanoma cells
title_fullStr Ultrarapid lytic granule release from CTLs activates Ca(2+)-dependent synaptic resistance pathways in melanoma cells
title_full_unstemmed Ultrarapid lytic granule release from CTLs activates Ca(2+)-dependent synaptic resistance pathways in melanoma cells
title_short Ultrarapid lytic granule release from CTLs activates Ca(2+)-dependent synaptic resistance pathways in melanoma cells
title_sort ultrarapid lytic granule release from ctls activates ca(2+)-dependent synaptic resistance pathways in melanoma cells
topic Biomedicine and Life Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8849291/
https://www.ncbi.nlm.nih.gov/pubmed/35171665
http://dx.doi.org/10.1126/sciadv.abk3234
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