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CD26-negative and CD26-positive tissue-resident fibroblasts contribute to functionally distinct CAF subpopulations in breast cancer

Author

Listed:
  • Julia M. Houthuijzen

    (The Netherlands Cancer Institute)

  • Roebi Bruijn

    (The Netherlands Cancer Institute
    The Netherlands Cancer Institute)

  • Eline Burg

    (The Netherlands Cancer Institute)

  • Anne Paulien Drenth

    (The Netherlands Cancer Institute)

  • Ellen Wientjens

    (The Netherlands Cancer Institute)

  • Tamara Filipovic

    (The Netherlands Cancer Institute)

  • Esme Bullock

    (University of Edinburgh)

  • Chiara S. Brambillasca

    (The Netherlands Cancer Institute)

  • Emilia M. Pulver

    (The Netherlands Cancer Institute)

  • Marja Nieuwland

    (Genomics Core Facility, The Netherlands Cancer Institute)

  • Iris Rink

    (Genomics Core Facility, The Netherlands Cancer Institute)

  • Frank Diepen

    (Flow Cytometry Facility, The Netherlands Cancer Institute)

  • Sjoerd Klarenbeek

    (The Netherlands Cancer Institute)

  • Ron Kerkhoven

    (Genomics Core Facility, The Netherlands Cancer Institute)

  • Valerie G. Brunton

    (University of Edinburgh)

  • Colinda L.G.J. Scheele

    (VIB Center for Cancer Biology, KU Leuven
    Department of Oncology, KU Leuven)

  • Mirjam C. Boelens

    (The Netherlands Cancer Institute)

  • Jos Jonkers

    (The Netherlands Cancer Institute)

Abstract

Cancer-associated fibroblasts (CAFs) are abundantly present in the microenvironment of virtually all tumors and strongly impact tumor progression. Despite increasing insight into their function and heterogeneity, little is known regarding the origin of CAFs. Understanding the origin of CAF heterogeneity is needed to develop successful CAF-based targeted therapies. Through various transplantation studies in mice, we show that CAFs in both invasive lobular breast cancer and triple-negative breast cancer originate from mammary tissue-resident normal fibroblasts (NFs). Single-cell transcriptomics, in vivo and in vitro studies reveal the transition of CD26+ and CD26- NF populations into inflammatory CAFs (iCAFs) and myofibroblastic CAFs (myCAFs), respectively. Functional co-culture experiments show that CD26+ NFs transition into pro-tumorigenic iCAFs which recruit myeloid cells in a CXCL12-dependent manner and enhance tumor cell invasion via matrix-metalloproteinase (MMP) activity. Together, our data suggest that CD26+ and CD26- NFs transform into distinct CAF subpopulations in mouse models of breast cancer.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-35793-w
    DOI: 10.1038/s41467-023-35793-w
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