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

Anne-Marie Givel, Yann Kieffer, Alix Scholer-Dahirel, Philemon Sirven, Melissa Cardon, Floriane Pelon, Ilaria Magagna, Géraldine Gentric, Ana Costa, Claire Bonneau, Virginie Mieulet, Anne Vincent-Salomon and Fatima Mechta-Grigoriou ()
Additional contact information
Anne-Marie Givel: PSL Research University
Yann Kieffer: PSL Research University
Alix Scholer-Dahirel: PSL Research University
Philemon Sirven: Inserm
Melissa Cardon: PSL Research University
Floriane Pelon: PSL Research University
Ilaria Magagna: PSL Research University
Géraldine Gentric: PSL Research University
Ana Costa: PSL Research University
Claire Bonneau: PSL Research University
Virginie Mieulet: PSL Research University
Anne Vincent-Salomon: Institut Curie Hospital Group
Fatima Mechta-Grigoriou: PSL Research University

Nature Communications, 2018, vol. 9, issue 1, 1-20

Abstract: Abstract 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.

Date: 2018
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DOI: 10.1038/s41467-018-03348-z

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