Targeting of the IL-33/Wnt axis restricts breast cancer stemness and metastasis
Abstract Interleukin-33 (IL-33) plays multifaceted roles in tumor progression, but its autocrine regulation of breast cancer stemness and metastasis via the Wnt pathway remains unclear. Here, we investigated the IL-33/ST2 axis in breast cancer using CRISPR/Cas9, single-cell RNA sequencing, and murin...
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Nature Portfolio
2025-05-01
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| Series: | Scientific Reports |
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| Online Access: | https://doi.org/10.1038/s41598-025-03260-9 |
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| author | Guanglin Fan Shuting Zuo Zhen Wang Siwei Zhang Liping Liu Haoge Luo Yingdong Xie Yan Zhang Dong Li |
| author_facet | Guanglin Fan Shuting Zuo Zhen Wang Siwei Zhang Liping Liu Haoge Luo Yingdong Xie Yan Zhang Dong Li |
| author_sort | Guanglin Fan |
| collection | DOAJ |
| description | Abstract Interleukin-33 (IL-33) plays multifaceted roles in tumor progression, but its autocrine regulation of breast cancer stemness and metastasis via the Wnt pathway remains unclear. Here, we investigated the IL-33/ST2 axis in breast cancer using CRISPR/Cas9, single-cell RNA sequencing, and murine models (orthotopic 4T1 and spontaneous MMTV-PyMT). Elevated IL-33 levels correlated with aggressive subtypes and poor prognosis. IL-33 overexpression enhanced proliferation, migration, and cancer stem cell (CSC) marker expression (CD44, ALDH1) in 4T1 and MDA-MB-231 cells, whereas ST2 knockdown via CRISPR or adeno-associated virus (AAV) attenuated tumor growth and metastasis in vivo, reducing CSC frequency. Mechanistically, IL-33 activated Wnt/β-catenin signaling to promote stemness, which was reversed by the Wnt inhibitor XAV-939. Single-cell analysis revealed that IL-33 overexpression skewed the immune microenvironment toward immunosuppression, while ST2 knockdown restored antitumor immunity. Our findings establish an IL-33–Wnt axis as a critical driver of breast cancer aggressiveness and propose AAV-mediated ST2 silencing as a novel therapeutic strategy. Targeting this axis may offer dual benefits by suppressing stemness and enhancing immune surveillance, warranting clinical exploration for advanced breast cancer. |
| format | Article |
| id | doaj-art-8d9ae65ee91b4a0a88d83e0cfcfed185 |
| institution | DOAJ |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj-art-8d9ae65ee91b4a0a88d83e0cfcfed1852025-08-20T03:08:40ZengNature PortfolioScientific Reports2045-23222025-05-0115111510.1038/s41598-025-03260-9Targeting of the IL-33/Wnt axis restricts breast cancer stemness and metastasisGuanglin Fan0Shuting Zuo1Zhen Wang2Siwei Zhang3Liping Liu4Haoge Luo5Yingdong Xie6Yan Zhang7Dong Li8Department of Breast Surgery, The Second Hospital of Jilin UniversityDepartment of Breast Surgery, The Second Hospital of Jilin UniversityDepartment of Breast Surgery, The Second Hospital of Jilin UniversityDepartment of Pharmacology, College of Basic Medical Sciences, Jilin UniversityDepartment of Immunology, College of Basic Medical Sciences, Jilin UniversityDepartment of Immunology, College of Basic Medical Sciences, Jilin UniversityDepartment of Immunology, College of Basic Medical Sciences, Jilin UniversityDepartment of Breast Surgery, The Second Hospital of Jilin UniversityDepartment of Immunology, College of Basic Medical Sciences, Jilin UniversityAbstract Interleukin-33 (IL-33) plays multifaceted roles in tumor progression, but its autocrine regulation of breast cancer stemness and metastasis via the Wnt pathway remains unclear. Here, we investigated the IL-33/ST2 axis in breast cancer using CRISPR/Cas9, single-cell RNA sequencing, and murine models (orthotopic 4T1 and spontaneous MMTV-PyMT). Elevated IL-33 levels correlated with aggressive subtypes and poor prognosis. IL-33 overexpression enhanced proliferation, migration, and cancer stem cell (CSC) marker expression (CD44, ALDH1) in 4T1 and MDA-MB-231 cells, whereas ST2 knockdown via CRISPR or adeno-associated virus (AAV) attenuated tumor growth and metastasis in vivo, reducing CSC frequency. Mechanistically, IL-33 activated Wnt/β-catenin signaling to promote stemness, which was reversed by the Wnt inhibitor XAV-939. Single-cell analysis revealed that IL-33 overexpression skewed the immune microenvironment toward immunosuppression, while ST2 knockdown restored antitumor immunity. Our findings establish an IL-33–Wnt axis as a critical driver of breast cancer aggressiveness and propose AAV-mediated ST2 silencing as a novel therapeutic strategy. Targeting this axis may offer dual benefits by suppressing stemness and enhancing immune surveillance, warranting clinical exploration for advanced breast cancer.https://doi.org/10.1038/s41598-025-03260-9IL-33ST2 knockdownBreast cancer stem cellsWnt pathwayImmunotherapy |
| spellingShingle | Guanglin Fan Shuting Zuo Zhen Wang Siwei Zhang Liping Liu Haoge Luo Yingdong Xie Yan Zhang Dong Li Targeting of the IL-33/Wnt axis restricts breast cancer stemness and metastasis Scientific Reports IL-33 ST2 knockdown Breast cancer stem cells Wnt pathway Immunotherapy |
| title | Targeting of the IL-33/Wnt axis restricts breast cancer stemness and metastasis |
| title_full | Targeting of the IL-33/Wnt axis restricts breast cancer stemness and metastasis |
| title_fullStr | Targeting of the IL-33/Wnt axis restricts breast cancer stemness and metastasis |
| title_full_unstemmed | Targeting of the IL-33/Wnt axis restricts breast cancer stemness and metastasis |
| title_short | Targeting of the IL-33/Wnt axis restricts breast cancer stemness and metastasis |
| title_sort | targeting of the il 33 wnt axis restricts breast cancer stemness and metastasis |
| topic | IL-33 ST2 knockdown Breast cancer stem cells Wnt pathway Immunotherapy |
| url | https://doi.org/10.1038/s41598-025-03260-9 |
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