PMN-MDSCs modulated by CCL20 from cancer cells promoted breast cancer cell stemness through CXCL2-CXCR2 pathway

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

doi:10.1038/s41392-023-01337-3

Signal Transduction and Targeted Therapy (Mar 2023)

PMN-MDSCs modulated by CCL20 from cancer cells promoted breast cancer cell stemness through CXCL2-CXCR2 pathway

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

Affiliations

Rui Zhang: Fudan 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 University
Mengxue Dong: Fudan 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 University
Juchuanli Tu: Fudan 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 University
Fengkai Li: Fudan 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 University
Qiaodan Deng: Fudan 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 University
Jiahui Xu: Fudan 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 University
Xueyan He: Fudan 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 University
Jiajun Ding: Fudan 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 University
Jie Xia: Fudan 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 University
Dandan Sheng: Fudan 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 University
Zhaoxia Chang: Fudan 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 University
Wei Ma: Fudan 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 University
Haonan Dong: Fudan 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 University
Yi Zhang: Department of Breast and Thyroid Surgery, Southwest Hospital, the First Affiliated Hospital of the Army Military Medical University
Lixing Zhang: Fudan 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 University
Lu Zhang: Fudan 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 University
Suling Liu: Fudan 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 University

DOI: https://doi.org/10.1038/s41392-023-01337-3
Journal volume & issue: Vol. 8, no. 1
pp. 1 – 14

Abstract

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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.

Published in Signal Transduction and Targeted Therapy

ISSN: 2059-3635 (Online)
Publisher: Nature Publishing Group
Country of publisher: United Kingdom
LCC subjects: Medicine; Science: Biology (General)
Website: http://www.nature.com/sigtrans/

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