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Stroma-derived Dickkopf-1 contributes to the suppression of NK cell cytotoxicity in breast cancer

Author

Listed:
  • Seunghyun Lee

    (Washington University School of Medicine)

  • Biancamaria Ricci

    (Washington University School of Medicine)

  • Jennifer Tran

    (Washington University School of Medicine)

  • Emily Eul

    (Washington University School of Medicine)

  • Jiayu Ye

    (Washington University School of Medicine)

  • Qihao Ren

    (Washington University School of Medicine)

  • David Clever

    (Washington University School of Medicine)

  • Julia Wang

    (Washington University School of Medicine
    Washington University in St. Louis)

  • Pamela Wong

    (Washington University School of Medicine)

  • Michael S. Haas

    (Leap Therapeutics)

  • Sheila A. Stewart

    (Washington University School of Medicine
    Washington University School of Medicine
    Washington University School of Medicine in St. Louis)

  • Cynthia X. Ma

    (Washington University School of Medicine
    Washington University School of Medicine in St. Louis)

  • Todd A. Fehniger

    (Washington University School of Medicine
    Washington University School of Medicine in St. Louis)

  • Roberta Faccio

    (Washington University School of Medicine
    Washington University School of Medicine in St. Louis
    Shriners Hospitals for Children St Louis)

Abstract

Mechanisms related to tumor evasion from NK cell-mediated immune surveillance remain enigmatic. Dickkopf-1 (DKK1) is a Wnt/β-catenin inhibitor, whose levels correlate with breast cancer progression. We find DKK1 to be expressed by tumor cells and cancer-associated fibroblasts (CAFs) in patient samples and orthotopic breast tumors, and in bone. By using genetic approaches, we find that bone-derived DKK1 contributes to the systemic DKK1 elevation in tumor-bearing female mice, while CAFs contribute to DKK1 at primary tumor site. Systemic and bone-specific DKK1 targeting reduce tumor growth. Intriguingly, deletion of CAF-derived DKK1 also limits breast cancer progression, without affecting its levels in circulation, and regardless of DKK1 expression in the tumor cells. While not directly supporting tumor proliferation, stromal-DKK1 suppresses NK cell activation and cytotoxicity by downregulating AKT/ERK/S6 phosphorylation. Importantly, increased DKK1 levels and reduced cytotoxic NK cells are detected in women with progressive breast cancer. Our findings indicate that DKK1 represents a barrier to anti-tumor immunity through suppression of NK cells.

Suggested Citation

  • Seunghyun Lee & Biancamaria Ricci & Jennifer Tran & Emily Eul & Jiayu Ye & Qihao Ren & David Clever & Julia Wang & Pamela Wong & Michael S. Haas & Sheila A. Stewart & Cynthia X. Ma & Todd A. Fehniger , 2025. "Stroma-derived Dickkopf-1 contributes to the suppression of NK cell cytotoxicity in breast cancer," Nature Communications, Nature, vol. 16(1), pages 1-19, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-56420-w
    DOI: 10.1038/s41467-025-56420-w
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    References listed on IDEAS

    as
    1. George C. Linderman & Jun Zhao & Manolis Roulis & Piotr Bielecki & Richard A. Flavell & Boaz Nadler & Yuval Kluger, 2022. "Zero-preserving imputation of single-cell RNA-seq data," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    2. Antoine E. Karnoub & Ajeeta B. Dash & Annie P. Vo & Andrew Sullivan & Mary W. Brooks & George W. Bell & Andrea L. Richardson & Kornelia Polyak & Ross Tubo & Robert A. Weinberg, 2007. "Mesenchymal stem cells within tumour stroma promote breast cancer metastasis," Nature, Nature, vol. 449(7162), pages 557-563, October.
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