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Cancer-associated fibroblast heterogeneity in axillary lymph nodes drives metastases in breast cancer through complementary mechanisms

Author

Listed:
  • Floriane Pelon

    (PSL Research University
    Inserm, U830)

  • Brigitte Bourachot

    (PSL Research University
    Inserm, U830)

  • Yann Kieffer

    (PSL Research University
    Inserm, U830)

  • Ilaria Magagna

    (PSL Research University
    Inserm, U830)

  • Fanny Mermet-Meillon

    (PSL Research University)

  • Isabelle Bonnet

    (PSL Research University, Sorbonne Université)

  • Ana Costa

    (PSL Research University
    Inserm, U830)

  • Anne-Marie Givel

    (PSL Research University
    Inserm, U830)

  • Youmna Attieh

    (PSL Research University)

  • Jorge Barbazan

    (PSL Research University)

  • Claire Bonneau

    (PSL Research University
    Inserm, U830)

  • Laetitia Fuhrmann

    (Institut Curie Hospital)

  • Stéphanie Descroix

    (Institut Pierre-Gilles de Gennes, CNRS UMR168)

  • Danijela Vignjevic

    (PSL Research University)

  • Pascal Silberzan

    (PSL Research University, Sorbonne Université)

  • Maria Carla Parrini

    (PSL Research University)

  • Anne Vincent-Salomon

    (Institut Curie Hospital)

  • Fatima Mechta-Grigoriou

    (PSL Research University
    Inserm, U830)

Abstract

Although fibroblast heterogeneity is recognized in primary tumors, both its characterization in and its impact on metastases remain unknown. Here, combining flow cytometry, immunohistochemistry and RNA-sequencing on breast cancer samples, we identify four Cancer-Associated Fibroblast (CAF) subpopulations in metastatic lymph nodes (LN). Two myofibroblastic subsets, CAF-S1 and CAF-S4, accumulate in LN and correlate with cancer cell invasion. By developing functional assays on primary cultures, we demonstrate that these subsets promote metastasis through distinct functions. While CAF-S1 stimulate cancer cell migration and initiate an epithelial-to-mesenchymal transition through CXCL12 and TGFβ pathways, highly contractile CAF-S4 induce cancer cell invasion in 3-dimensions via NOTCH signaling. Patients with high levels of CAFs, particularly CAF-S4, in LN at diagnosis are prone to develop late distant metastases. Our findings suggest that CAF subset accumulation in LN is a prognostic marker, suggesting that CAF subsets could be examined in axillary LN at diagnosis.

Suggested Citation

  • Floriane Pelon & Brigitte Bourachot & Yann Kieffer & Ilaria Magagna & Fanny Mermet-Meillon & Isabelle Bonnet & Ana Costa & Anne-Marie Givel & Youmna Attieh & Jorge Barbazan & Claire Bonneau & Laetitia, 2020. "Cancer-associated fibroblast heterogeneity in axillary lymph nodes drives metastases in breast cancer through complementary mechanisms," Nature Communications, Nature, vol. 11(1), pages 1-20, December.
  • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-019-14134-w
    DOI: 10.1038/s41467-019-14134-w
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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.
    2. Lena Cords & Sandra Tietscher & Tobias Anzeneder & Claus Langwieder & Martin Rees & Natalie Souza & Bernd Bodenmiller, 2023. "Cancer-associated fibroblast classification in single-cell and spatial proteomics data," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    3. Hugo Croizer & Rana Mhaidly & Yann Kieffer & Geraldine Gentric & Lounes Djerroudi & Renaud Leclere & Floriane Pelon & Catherine Robley & Mylene Bohec & Arnaud Meng & Didier Meseure & Emanuela Romano &, 2024. "Deciphering the spatial landscape and plasticity of immunosuppressive fibroblasts in breast cancer," Nature Communications, Nature, vol. 15(1), pages 1-28, December.
    4. Julia M. Houthuijzen & Roebi Bruijn & Eline Burg & Anne Paulien Drenth & Ellen Wientjens & Tamara Filipovic & Esme Bullock & Chiara S. Brambillasca & Emilia M. Pulver & Marja Nieuwland & Iris Rink & F, 2023. "CD26-negative and CD26-positive tissue-resident fibroblasts contribute to functionally distinct CAF subpopulations in breast cancer," Nature Communications, Nature, vol. 14(1), pages 1-21, December.
    5. Monika Licaj & Rana Mhaidly & Yann Kieffer & Hugo Croizer & Claire Bonneau & Arnaud Meng & Lounes Djerroudi & Kevin Mujangi-Ebeka & Hocine R. Hocine & Brigitte Bourachot & Ilaria Magagna & Renaud Lecl, 2024. "Residual ANTXR1+ myofibroblasts after chemotherapy inhibit anti-tumor immunity via YAP1 signaling pathway," Nature Communications, Nature, vol. 15(1), pages 1-27, December.
    6. Elisa I. Rivas & Jenniffer Linares & Melissa Zwick & Andrea Gómez-Llonin & Marc Guiu & Anna Labernadie & Jordi Badia-Ramentol & Anna Lladó & Lídia Bardia & Iván Pérez-Núñez & Carolina Martínez-Ciarpag, 2022. "Targeted immunotherapy against distinct cancer-associated fibroblasts overcomes treatment resistance in refractory HER2+ breast tumors," Nature Communications, Nature, vol. 13(1), pages 1-16, December.

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