Stroma-derived Dickkopf-1 contributes to the suppression of NK cell cytotoxicity in breast cancer
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 pati...
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Nature Portfolio
2025-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-56420-w |
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| author | 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 Roberta Faccio |
| author_facet | 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 Roberta Faccio |
| author_sort | Seunghyun Lee |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-115f0a936c0f487cb6c72ae68ef97029 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-115f0a936c0f487cb6c72ae68ef970292025-02-02T12:32:02ZengNature PortfolioNature Communications2041-17232025-01-0116111910.1038/s41467-025-56420-wStroma-derived Dickkopf-1 contributes to the suppression of NK cell cytotoxicity in breast cancerSeunghyun Lee0Biancamaria Ricci1Jennifer Tran2Emily Eul3Jiayu Ye4Qihao Ren5David Clever6Julia Wang7Pamela Wong8Michael S. Haas9Sheila A. Stewart10Cynthia X. Ma11Todd A. Fehniger12Roberta Faccio13Department of Orthopaedic Surgery, Washington University School of MedicineDepartment of Orthopaedic Surgery, Washington University School of MedicineDepartment of Medicine, Washington University School of MedicineDepartment of Orthopaedic Surgery, Washington University School of MedicineDepartment of Cell Biology and Physiology, Washington University School of MedicineDepartment of Cell Biology and Physiology, Washington University School of MedicineDepartment of Orthopaedic Surgery, Washington University School of MedicineDepartment of Medicine, Washington University School of MedicineDepartment of Medicine, Washington University School of MedicineLeap TherapeuticsDepartment of Medicine, Washington University School of MedicineDepartment of Medicine, Washington University School of MedicineDepartment of Medicine, Washington University School of MedicineDepartment of Orthopaedic Surgery, Washington University School of MedicineAbstract 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.https://doi.org/10.1038/s41467-025-56420-w |
| spellingShingle | 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 Roberta Faccio Stroma-derived Dickkopf-1 contributes to the suppression of NK cell cytotoxicity in breast cancer Nature Communications |
| title | Stroma-derived Dickkopf-1 contributes to the suppression of NK cell cytotoxicity in breast cancer |
| title_full | Stroma-derived Dickkopf-1 contributes to the suppression of NK cell cytotoxicity in breast cancer |
| title_fullStr | Stroma-derived Dickkopf-1 contributes to the suppression of NK cell cytotoxicity in breast cancer |
| title_full_unstemmed | Stroma-derived Dickkopf-1 contributes to the suppression of NK cell cytotoxicity in breast cancer |
| title_short | Stroma-derived Dickkopf-1 contributes to the suppression of NK cell cytotoxicity in breast cancer |
| title_sort | stroma derived dickkopf 1 contributes to the suppression of nk cell cytotoxicity in breast cancer |
| url | https://doi.org/10.1038/s41467-025-56420-w |
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