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Cellular Heterogeneity and Cooperativity in Glioma Persister Cells Under Temozolomide Treatment

We have observed a drug-tolerant/persister state in a human glioblastoma (GBM) cell line after exposure to temozolomide, the standard-of-care chemotherapeutic agent for GBM. We used a multicolor lentiviral genetic barcode labeling to follow cell population evolution during temozolomide treatment. We...

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Autores principales: Rabé, Marion, Fonteneau, Lucie, Oliver, Lisa, Morales-Molina, Alvaro, Jubelin, Camille, Garcia-Castro, Javier, Heymann, Dominique, Gratas, Catherine, Vallette, François M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9174429/
https://www.ncbi.nlm.nih.gov/pubmed/35693929
http://dx.doi.org/10.3389/fcell.2022.835273
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author Rabé, Marion
Fonteneau, Lucie
Oliver, Lisa
Morales-Molina, Alvaro
Jubelin, Camille
Garcia-Castro, Javier
Heymann, Dominique
Gratas, Catherine
Vallette, François M.
author_facet Rabé, Marion
Fonteneau, Lucie
Oliver, Lisa
Morales-Molina, Alvaro
Jubelin, Camille
Garcia-Castro, Javier
Heymann, Dominique
Gratas, Catherine
Vallette, François M.
author_sort Rabé, Marion
collection PubMed
description We have observed a drug-tolerant/persister state in a human glioblastoma (GBM) cell line after exposure to temozolomide, the standard-of-care chemotherapeutic agent for GBM. We used a multicolor lentiviral genetic barcode labeling to follow cell population evolution during temozolomide treatment. We observed no change in the distribution of the different colored populations of cells in persister or resistant cells suggesting that pre-existing minor subpopulations, which would be expected to be restricted to a single color, were not amplified/selected during the response to the drug. We have previously identified four genes (CHI3L1, FAT2, KLK5, and HB-EGF) that were over-expressed during the persister stage. Single-cell analysis of these four genes indicated that they were expressed in different individual cells ruling out the existence of a single persister-specific clone but suggesting rather a global answer. Even so, the transitory silencing of CHI3L1, FAT2, or KLK5 influenced the expression of the other three genes and the survival of U251 cells in absence of temozolomide. Since proteins encoded by the four genes are all localized in the extracellular matrix or interact within the extracellular compartment, we propose that cellular interactions and communications are important during the persister stage before the acquisition of chemo-resistance. Thus, persisters might be a new therapeutically relevant target in GBM.
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spelling pubmed-91744292022-06-09 Cellular Heterogeneity and Cooperativity in Glioma Persister Cells Under Temozolomide Treatment Rabé, Marion Fonteneau, Lucie Oliver, Lisa Morales-Molina, Alvaro Jubelin, Camille Garcia-Castro, Javier Heymann, Dominique Gratas, Catherine Vallette, François M. Front Cell Dev Biol Cell and Developmental Biology We have observed a drug-tolerant/persister state in a human glioblastoma (GBM) cell line after exposure to temozolomide, the standard-of-care chemotherapeutic agent for GBM. We used a multicolor lentiviral genetic barcode labeling to follow cell population evolution during temozolomide treatment. We observed no change in the distribution of the different colored populations of cells in persister or resistant cells suggesting that pre-existing minor subpopulations, which would be expected to be restricted to a single color, were not amplified/selected during the response to the drug. We have previously identified four genes (CHI3L1, FAT2, KLK5, and HB-EGF) that were over-expressed during the persister stage. Single-cell analysis of these four genes indicated that they were expressed in different individual cells ruling out the existence of a single persister-specific clone but suggesting rather a global answer. Even so, the transitory silencing of CHI3L1, FAT2, or KLK5 influenced the expression of the other three genes and the survival of U251 cells in absence of temozolomide. Since proteins encoded by the four genes are all localized in the extracellular matrix or interact within the extracellular compartment, we propose that cellular interactions and communications are important during the persister stage before the acquisition of chemo-resistance. Thus, persisters might be a new therapeutically relevant target in GBM. Frontiers Media S.A. 2022-05-25 /pmc/articles/PMC9174429/ /pubmed/35693929 http://dx.doi.org/10.3389/fcell.2022.835273 Text en Copyright © 2022 Rabé, Fonteneau, Oliver, Morales-Molina, Jubelin, Garcia-Castro, Heymann, Gratas and Vallette. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Cell and Developmental Biology
Rabé, Marion
Fonteneau, Lucie
Oliver, Lisa
Morales-Molina, Alvaro
Jubelin, Camille
Garcia-Castro, Javier
Heymann, Dominique
Gratas, Catherine
Vallette, François M.
Cellular Heterogeneity and Cooperativity in Glioma Persister Cells Under Temozolomide Treatment
title Cellular Heterogeneity and Cooperativity in Glioma Persister Cells Under Temozolomide Treatment
title_full Cellular Heterogeneity and Cooperativity in Glioma Persister Cells Under Temozolomide Treatment
title_fullStr Cellular Heterogeneity and Cooperativity in Glioma Persister Cells Under Temozolomide Treatment
title_full_unstemmed Cellular Heterogeneity and Cooperativity in Glioma Persister Cells Under Temozolomide Treatment
title_short Cellular Heterogeneity and Cooperativity in Glioma Persister Cells Under Temozolomide Treatment
title_sort cellular heterogeneity and cooperativity in glioma persister cells under temozolomide treatment
topic Cell and Developmental Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9174429/
https://www.ncbi.nlm.nih.gov/pubmed/35693929
http://dx.doi.org/10.3389/fcell.2022.835273
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