PMN-MDSCs modulated by CCL20 from cancer cells promoted breast cancer cell stemness through CXCL2-CXCR2 pathway
Abstract Our previous studies have showed that C-C motif chemokine ligand 20 (CCL20) advanced tumor progression and enhanced the chemoresistance of cancer cells by positively regulating breast cancer stem cell (BCSC) self-renewal. However, it is unclear whether CCL20 affects breast cancer progressio...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2023-03-01
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| Series: | Signal Transduction and Targeted Therapy |
| Online Access: | https://doi.org/10.1038/s41392-023-01337-3 |
| _version_ | 1797863411356270592 |
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| author | Rui Zhang Mengxue Dong Juchuanli Tu Fengkai Li Qiaodan Deng Jiahui Xu Xueyan He Jiajun Ding Jie Xia Dandan Sheng Zhaoxia Chang Wei Ma Haonan Dong Yi Zhang Lixing Zhang Lu Zhang Suling Liu |
| author_facet | Rui Zhang Mengxue Dong Juchuanli Tu Fengkai Li Qiaodan Deng Jiahui Xu Xueyan He Jiajun Ding Jie Xia Dandan Sheng Zhaoxia Chang Wei Ma Haonan Dong Yi Zhang Lixing Zhang Lu Zhang Suling Liu |
| author_sort | Rui Zhang |
| collection | DOAJ |
| description | Abstract Our previous studies have showed that C-C motif chemokine ligand 20 (CCL20) advanced tumor progression and enhanced the chemoresistance of cancer cells by positively regulating breast cancer stem cell (BCSC) self-renewal. However, it is unclear whether CCL20 affects breast cancer progression by remodeling the tumor microenvironment (TME). Here, we observed that polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) were remarkably enriched in TME of CCL20-overexpressing cancer cell orthotopic allograft tumors. Mechanistically, CCL20 activated the differentiation of granulocyte-monocyte progenitors (GMPs) via its receptor C-C motif chemokine receptor 6 (CCR6) leading to the PMN-MDSC expansion. PMN-MDSCs from CCL20-overexpressing cell orthotopic allograft tumors (CCL20-modulated PMN-MDSCs) secreted amounts of C-X-C motif chemokine ligand 2 (CXCL2) and increased ALDH+ BCSCs via activating CXCR2/NOTCH1/HEY1 signaling pathway. Furthermore, C-X-C motif chemokine receptor 2 (CXCR2) antagonist SB225002 enhanced the docetaxel (DTX) effects on tumor growth by decreasing BCSCs in CCL20high-expressing tumors. These findings elucidated how CCL20 modulated the TME to promote cancer development, indicating a new therapeutic strategy by interfering with the interaction between PMN-MDSCs and BCSCs in breast cancer, especially in CCL20high-expressing breast cancer. |
| first_indexed | 2024-04-09T22:36:12Z |
| format | Article |
| id | doaj.art-9223a8c700cb4717adae1b2da7a6fce0 |
| institution | Directory Open Access Journal |
| issn | 2059-3635 |
| language | English |
| last_indexed | 2024-04-09T22:36:12Z |
| publishDate | 2023-03-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Signal Transduction and Targeted Therapy |
| spelling | doaj.art-9223a8c700cb4717adae1b2da7a6fce02023-03-22T12:30:47ZengNature Publishing GroupSignal Transduction and Targeted Therapy2059-36352023-03-018111410.1038/s41392-023-01337-3PMN-MDSCs modulated by CCL20 from cancer cells promoted breast cancer cell stemness through CXCL2-CXCR2 pathwayRui Zhang0Mengxue Dong1Juchuanli Tu2Fengkai Li3Qiaodan Deng4Jiahui Xu5Xueyan He6Jiajun Ding7Jie Xia8Dandan Sheng9Zhaoxia Chang10Wei Ma11Haonan Dong12Yi Zhang13Lixing Zhang14Lu Zhang15Suling Liu16Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences; State Key Laboratory of Genetic Engineering; Cancer Institutes; Key Laboratory of Breast Cancer in Shanghai; The Shanghai Key Laboratory of Medical Epigenetics; Shanghai Key Laboratory of Radiation Oncology; The International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology; Shanghai Medical College; Fudan UniversityFudan University Shanghai Cancer Center & Institutes of Biomedical Sciences; State Key Laboratory of Genetic Engineering; Cancer Institutes; Key Laboratory of Breast Cancer in Shanghai; The Shanghai Key Laboratory of Medical Epigenetics; Shanghai Key Laboratory of Radiation Oncology; The International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology; Shanghai Medical College; Fudan UniversityFudan University Shanghai Cancer Center & Institutes of Biomedical Sciences; State Key Laboratory of Genetic Engineering; Cancer Institutes; Key Laboratory of Breast Cancer in Shanghai; The Shanghai Key Laboratory of Medical Epigenetics; Shanghai Key Laboratory of Radiation Oncology; The International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology; Shanghai Medical College; Fudan UniversityFudan University Shanghai Cancer Center & Institutes of Biomedical Sciences; State Key Laboratory of Genetic Engineering; Cancer Institutes; Key Laboratory of Breast Cancer in Shanghai; The Shanghai Key Laboratory of Medical Epigenetics; Shanghai Key Laboratory of Radiation Oncology; The International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology; Shanghai Medical College; Fudan UniversityFudan University Shanghai Cancer Center & Institutes of Biomedical Sciences; State Key Laboratory of Genetic Engineering; Cancer Institutes; Key Laboratory of Breast Cancer in Shanghai; The Shanghai Key Laboratory of Medical Epigenetics; Shanghai Key Laboratory of Radiation Oncology; The International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology; Shanghai Medical College; Fudan UniversityFudan University Shanghai Cancer Center & Institutes of Biomedical Sciences; State Key Laboratory of Genetic Engineering; Cancer Institutes; Key Laboratory of Breast Cancer in Shanghai; The Shanghai Key Laboratory of Medical Epigenetics; Shanghai Key Laboratory of Radiation Oncology; The International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology; Shanghai Medical College; Fudan UniversityFudan University Shanghai Cancer Center & Institutes of Biomedical Sciences; State Key Laboratory of Genetic Engineering; Cancer Institutes; Key Laboratory of Breast Cancer in Shanghai; The Shanghai Key Laboratory of Medical Epigenetics; Shanghai Key Laboratory of Radiation Oncology; The International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology; Shanghai Medical College; Fudan UniversityFudan University Shanghai Cancer Center & Institutes of Biomedical Sciences; State Key Laboratory of Genetic Engineering; Cancer Institutes; Key Laboratory of Breast Cancer in Shanghai; The Shanghai Key Laboratory of Medical Epigenetics; Shanghai Key Laboratory of Radiation Oncology; The International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology; Shanghai Medical College; Fudan UniversityFudan University Shanghai Cancer Center & Institutes of Biomedical Sciences; State Key Laboratory of Genetic Engineering; Cancer Institutes; Key Laboratory of Breast Cancer in Shanghai; The Shanghai Key Laboratory of Medical Epigenetics; Shanghai Key Laboratory of Radiation Oncology; The International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology; Shanghai Medical College; Fudan UniversityFudan University Shanghai Cancer Center & Institutes of Biomedical Sciences; State Key Laboratory of Genetic Engineering; Cancer Institutes; Key Laboratory of Breast Cancer in Shanghai; The Shanghai Key Laboratory of Medical Epigenetics; Shanghai Key Laboratory of Radiation Oncology; The International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology; Shanghai Medical College; Fudan UniversityFudan University Shanghai Cancer Center & Institutes of Biomedical Sciences; State Key Laboratory of Genetic Engineering; Cancer Institutes; Key Laboratory of Breast Cancer in Shanghai; The Shanghai Key Laboratory of Medical Epigenetics; Shanghai Key Laboratory of Radiation Oncology; The International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology; Shanghai Medical College; Fudan UniversityFudan University Shanghai Cancer Center & Institutes of Biomedical Sciences; State Key Laboratory of Genetic Engineering; Cancer Institutes; Key Laboratory of Breast Cancer in Shanghai; The Shanghai Key Laboratory of Medical Epigenetics; Shanghai Key Laboratory of Radiation Oncology; The International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology; Shanghai Medical College; Fudan UniversityFudan University Shanghai Cancer Center & Institutes of Biomedical Sciences; State Key Laboratory of Genetic Engineering; Cancer Institutes; Key Laboratory of Breast Cancer in Shanghai; The Shanghai Key Laboratory of Medical Epigenetics; Shanghai Key Laboratory of Radiation Oncology; The International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology; Shanghai Medical College; Fudan UniversityDepartment of Breast and Thyroid Surgery, Southwest Hospital, the First Affiliated Hospital of the Army Military Medical UniversityFudan University Shanghai Cancer Center & Institutes of Biomedical Sciences; State Key Laboratory of Genetic Engineering; Cancer Institutes; Key Laboratory of Breast Cancer in Shanghai; The Shanghai Key Laboratory of Medical Epigenetics; Shanghai Key Laboratory of Radiation Oncology; The International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology; Shanghai Medical College; Fudan UniversityFudan University Shanghai Cancer Center & Institutes of Biomedical Sciences; State Key Laboratory of Genetic Engineering; Cancer Institutes; Key Laboratory of Breast Cancer in Shanghai; The Shanghai Key Laboratory of Medical Epigenetics; Shanghai Key Laboratory of Radiation Oncology; The International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology; Shanghai Medical College; Fudan UniversityFudan University Shanghai Cancer Center & Institutes of Biomedical Sciences; State Key Laboratory of Genetic Engineering; Cancer Institutes; Key Laboratory of Breast Cancer in Shanghai; The Shanghai Key Laboratory of Medical Epigenetics; Shanghai Key Laboratory of Radiation Oncology; The International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology; Shanghai Medical College; Fudan UniversityAbstract Our previous studies have showed that C-C motif chemokine ligand 20 (CCL20) advanced tumor progression and enhanced the chemoresistance of cancer cells by positively regulating breast cancer stem cell (BCSC) self-renewal. However, it is unclear whether CCL20 affects breast cancer progression by remodeling the tumor microenvironment (TME). Here, we observed that polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) were remarkably enriched in TME of CCL20-overexpressing cancer cell orthotopic allograft tumors. Mechanistically, CCL20 activated the differentiation of granulocyte-monocyte progenitors (GMPs) via its receptor C-C motif chemokine receptor 6 (CCR6) leading to the PMN-MDSC expansion. PMN-MDSCs from CCL20-overexpressing cell orthotopic allograft tumors (CCL20-modulated PMN-MDSCs) secreted amounts of C-X-C motif chemokine ligand 2 (CXCL2) and increased ALDH+ BCSCs via activating CXCR2/NOTCH1/HEY1 signaling pathway. Furthermore, C-X-C motif chemokine receptor 2 (CXCR2) antagonist SB225002 enhanced the docetaxel (DTX) effects on tumor growth by decreasing BCSCs in CCL20high-expressing tumors. These findings elucidated how CCL20 modulated the TME to promote cancer development, indicating a new therapeutic strategy by interfering with the interaction between PMN-MDSCs and BCSCs in breast cancer, especially in CCL20high-expressing breast cancer.https://doi.org/10.1038/s41392-023-01337-3 |
| spellingShingle | Rui Zhang Mengxue Dong Juchuanli Tu Fengkai Li Qiaodan Deng Jiahui Xu Xueyan He Jiajun Ding Jie Xia Dandan Sheng Zhaoxia Chang Wei Ma Haonan Dong Yi Zhang Lixing Zhang Lu Zhang Suling Liu PMN-MDSCs modulated by CCL20 from cancer cells promoted breast cancer cell stemness through CXCL2-CXCR2 pathway Signal Transduction and Targeted Therapy |
| title | PMN-MDSCs modulated by CCL20 from cancer cells promoted breast cancer cell stemness through CXCL2-CXCR2 pathway |
| title_full | PMN-MDSCs modulated by CCL20 from cancer cells promoted breast cancer cell stemness through CXCL2-CXCR2 pathway |
| title_fullStr | PMN-MDSCs modulated by CCL20 from cancer cells promoted breast cancer cell stemness through CXCL2-CXCR2 pathway |
| title_full_unstemmed | PMN-MDSCs modulated by CCL20 from cancer cells promoted breast cancer cell stemness through CXCL2-CXCR2 pathway |
| title_short | PMN-MDSCs modulated by CCL20 from cancer cells promoted breast cancer cell stemness through CXCL2-CXCR2 pathway |
| title_sort | pmn mdscs modulated by ccl20 from cancer cells promoted breast cancer cell stemness through cxcl2 cxcr2 pathway |
| url | https://doi.org/10.1038/s41392-023-01337-3 |
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