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

Author

Listed:
  • Anne-Marie Givel

    (PSL Research University
    Inserm)

  • Yann Kieffer

    (PSL Research University
    Inserm)

  • Alix Scholer-Dahirel

    (PSL Research University
    Inserm)

  • Philemon Sirven

    (Inserm)

  • Melissa Cardon

    (PSL Research University
    Inserm)

  • Floriane Pelon

    (PSL Research University
    Inserm)

  • Ilaria Magagna

    (PSL Research University
    Inserm)

  • Géraldine Gentric

    (PSL Research University
    Inserm)

  • Ana Costa

    (PSL Research University
    Inserm)

  • Claire Bonneau

    (PSL Research University
    Inserm)

  • Virginie Mieulet

    (PSL Research University
    Inserm)

  • Anne Vincent-Salomon

    (Institut Curie Hospital Group)

  • Fatima Mechta-Grigoriou

    (PSL Research University
    Inserm)

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.

Suggested Citation

  • 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 V, 2018. "miR200-regulated CXCL12β promotes fibroblast heterogeneity and immunosuppression in ovarian cancers," Nature Communications, Nature, vol. 9(1), pages 1-20, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-03348-z
    DOI: 10.1038/s41467-018-03348-z
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    Cited by:

    1. Camille Cohen & Rana Mhaidly & Hugo Croizer & Yann Kieffer & Renaud Leclere & Anne Vincent-Salomon & Catherine Robley & Dany Anglicheau & Marion Rabant & Aurélie Sannier & Marc-Olivier Timsit & Sean E, 2024. "WNT-dependent interaction between inflammatory fibroblasts and FOLR2+ macrophages promotes fibrosis in chronic kidney disease," Nature Communications, Nature, vol. 15(1), pages 1-23, December.

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