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miR200-regulated CXCL12β promotes fibroblast heterogeneity and immunosuppression in ovarian cancers

High-grade serous ovarian cancers (HGSOC) have been subdivided into molecular subtypes. The mesenchymal HGSOC subgroup, defined by stromal-related gene signatures, is invariably associated with poor patient survival. We demonstrate that stroma exerts a key function in mesenchymal HGSOC. We highlight...

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Autores principales: Givel, Anne-Marie, Kieffer, Yann, Scholer-Dahirel, Alix, Sirven, Philemon, Cardon, Melissa, Pelon, Floriane, Magagna, Ilaria, Gentric, Géraldine, Costa, Ana, Bonneau, Claire, Mieulet, Virginie, Vincent-Salomon, Anne, Mechta-Grigoriou, Fatima
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5849633/
https://www.ncbi.nlm.nih.gov/pubmed/29535360
http://dx.doi.org/10.1038/s41467-018-03348-z
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author Givel, Anne-Marie
Kieffer, Yann
Scholer-Dahirel, Alix
Sirven, Philemon
Cardon, Melissa
Pelon, Floriane
Magagna, Ilaria
Gentric, Géraldine
Costa, Ana
Bonneau, Claire
Mieulet, Virginie
Vincent-Salomon, Anne
Mechta-Grigoriou, Fatima
author_facet Givel, Anne-Marie
Kieffer, Yann
Scholer-Dahirel, Alix
Sirven, Philemon
Cardon, Melissa
Pelon, Floriane
Magagna, Ilaria
Gentric, Géraldine
Costa, Ana
Bonneau, Claire
Mieulet, Virginie
Vincent-Salomon, Anne
Mechta-Grigoriou, Fatima
author_sort Givel, Anne-Marie
collection PubMed
description High-grade serous ovarian cancers (HGSOC) have been subdivided into molecular subtypes. The mesenchymal HGSOC subgroup, defined by stromal-related gene signatures, is invariably associated with poor patient survival. We demonstrate that stroma exerts a key function in mesenchymal HGSOC. We highlight stromal heterogeneity in HGSOC by identifying four subsets of carcinoma-associated fibroblasts (CAF-S1-4). Mesenchymal HGSOC show high content in CAF-S1 fibroblasts, which exhibit immunosuppressive functions by increasing attraction, survival, and differentiation of CD25(+)FOXP3(+) T lymphocytes. The beta isoform of the CXCL12 chemokine (CXCL12β) specifically accumulates in the immunosuppressive CAF-S1 subset through a miR-141/200a dependent-mechanism. Moreover, CXCL12β expression in CAF-S1 cells plays a crucial role in CAF-S1 immunosuppressive activity and is a reliable prognosis factor in HGSOC, in contrast to CXCL12α. Thus, our data highlight the differential regulation of the CXCL12α and CXCL12β isoforms in HGSOC, and reveal a CXCL12β-associated stromal heterogeneity and immunosuppressive environment in mesenchymal HGSOC.
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spelling pubmed-58496332018-03-15 miR200-regulated CXCL12β promotes fibroblast heterogeneity and immunosuppression in ovarian cancers Givel, Anne-Marie Kieffer, Yann Scholer-Dahirel, Alix Sirven, Philemon Cardon, Melissa Pelon, Floriane Magagna, Ilaria Gentric, Géraldine Costa, Ana Bonneau, Claire Mieulet, Virginie Vincent-Salomon, Anne Mechta-Grigoriou, Fatima Nat Commun Article High-grade serous ovarian cancers (HGSOC) have been subdivided into molecular subtypes. The mesenchymal HGSOC subgroup, defined by stromal-related gene signatures, is invariably associated with poor patient survival. We demonstrate that stroma exerts a key function in mesenchymal HGSOC. We highlight stromal heterogeneity in HGSOC by identifying four subsets of carcinoma-associated fibroblasts (CAF-S1-4). Mesenchymal HGSOC show high content in CAF-S1 fibroblasts, which exhibit immunosuppressive functions by increasing attraction, survival, and differentiation of CD25(+)FOXP3(+) T lymphocytes. The beta isoform of the CXCL12 chemokine (CXCL12β) specifically accumulates in the immunosuppressive CAF-S1 subset through a miR-141/200a dependent-mechanism. Moreover, CXCL12β expression in CAF-S1 cells plays a crucial role in CAF-S1 immunosuppressive activity and is a reliable prognosis factor in HGSOC, in contrast to CXCL12α. Thus, our data highlight the differential regulation of the CXCL12α and CXCL12β isoforms in HGSOC, and reveal a CXCL12β-associated stromal heterogeneity and immunosuppressive environment in mesenchymal HGSOC. Nature Publishing Group UK 2018-03-13 /pmc/articles/PMC5849633/ /pubmed/29535360 http://dx.doi.org/10.1038/s41467-018-03348-z Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Givel, Anne-Marie
Kieffer, Yann
Scholer-Dahirel, Alix
Sirven, Philemon
Cardon, Melissa
Pelon, Floriane
Magagna, Ilaria
Gentric, Géraldine
Costa, Ana
Bonneau, Claire
Mieulet, Virginie
Vincent-Salomon, Anne
Mechta-Grigoriou, Fatima
miR200-regulated CXCL12β promotes fibroblast heterogeneity and immunosuppression in ovarian cancers
title miR200-regulated CXCL12β promotes fibroblast heterogeneity and immunosuppression in ovarian cancers
title_full miR200-regulated CXCL12β promotes fibroblast heterogeneity and immunosuppression in ovarian cancers
title_fullStr miR200-regulated CXCL12β promotes fibroblast heterogeneity and immunosuppression in ovarian cancers
title_full_unstemmed miR200-regulated CXCL12β promotes fibroblast heterogeneity and immunosuppression in ovarian cancers
title_short miR200-regulated CXCL12β promotes fibroblast heterogeneity and immunosuppression in ovarian cancers
title_sort mir200-regulated cxcl12β promotes fibroblast heterogeneity and immunosuppression in ovarian cancers
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5849633/
https://www.ncbi.nlm.nih.gov/pubmed/29535360
http://dx.doi.org/10.1038/s41467-018-03348-z
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