The Zeb1-Cxcl1 axis impairs the antitumor immune response by inducing M2 macrophage polarization in breast cancer

Zeb1, a key epithelial-mesenchymal transition (EMT) regulator, has recently been found to be involved in M2 macrophage polarization in the tumor immune microenvironment, thereby promoting tumor development. However, the underlying mechanism of Zeb1-induced M2 macrophage polarization remains largely...

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Published inAmerican journal of cancer research Vol. 14; no. 9; pp. 4378 - 4397
Main Authors Ou, Yang, Jiang, Hui-Min, Wang, Yan-Jing, Shuai, Qiu-Ying, Cao, Li-Xia, Guo, Min, Qi, Chun-Chun, Li, Zhao-Xian, Shi, Jie, Hu, Hua-Yu, Liu, Yu-Xin, Zuo, Si-Yu, Chen, Xiao, Feng, Meng-Dan, Shi, Yi, Sun, Pei-Qing, Wang, Hang, Yang, Shuang
Format Journal Article
LanguageEnglish
Published United States e-Century Publishing Corporation 01.01.2024
Subjects
Original
Zeb1
M2 macrophage polarization
antitumor immune response
Breast cancer
Cxcl1
tumor immune microenvironment
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Abstract Zeb1, a key epithelial-mesenchymal transition (EMT) regulator, has recently been found to be involved in M2 macrophage polarization in the tumor immune microenvironment, thereby promoting tumor development. However, the underlying mechanism of Zeb1-induced M2 macrophage polarization remains largely unexplored. To identify the potential role of Zeb1 in remodeling the tumor immune microenvironment in breast cancer, we crossed the floxed Zeb1 allele homozygously into PyMT mice to generate PyMT; (MMTV-Cre;PyMT; ) mice. We found that the recruitment of M2-type tumor-associated macrophages (TAMs) was significantly reduced in tumors from PyMT; mice, and their tumor suppressive effects were weakened. Mechanistically, Zeb1 played a crucial role in transcriptionally promoting the production of Cxcl1 in tumor cells. In turn, Cxcl1 activated the Cxcr2-Jak-Stat3 pathway to induce M2 polarization of TAMs in a paracrine manner, which eventually led to T-cell inactivation and impaired the antitumor immune response in breast cancer. Our results collectively revealed an important role of Zeb1 in remodeling the tumor microenvironment, suggesting a novel therapeutic intervention for the treatment of advanced breast cancer.
AbstractList Zeb1, a key epithelial-mesenchymal transition (EMT) regulator, has recently been found to be involved in M2 macrophage polarization in the tumor immune microenvironment, thereby promoting tumor development. However, the underlying mechanism of Zeb1-induced M2 macrophage polarization remains largely unexplored. To identify the potential role of Zeb1 in remodeling the tumor immune microenvironment in breast cancer, we crossed the floxed Zeb1 allele homozygously into PyMT mice to generate PyMT; (MMTV-Cre;PyMT; ) mice. We found that the recruitment of M2-type tumor-associated macrophages (TAMs) was significantly reduced in tumors from PyMT; mice, and their tumor suppressive effects were weakened. Mechanistically, Zeb1 played a crucial role in transcriptionally promoting the production of Cxcl1 in tumor cells. In turn, Cxcl1 activated the Cxcr2-Jak-Stat3 pathway to induce M2 polarization of TAMs in a paracrine manner, which eventually led to T-cell inactivation and impaired the antitumor immune response in breast cancer. Our results collectively revealed an important role of Zeb1 in remodeling the tumor microenvironment, suggesting a novel therapeutic intervention for the treatment of advanced breast cancer.
Zeb1, a key epithelial-mesenchymal transition (EMT) regulator, has recently been found to be involved in M2 macrophage polarization in the tumor immune microenvironment, thereby promoting tumor development. However, the underlying mechanism of Zeb1-induced M2 macrophage polarization remains largely unexplored. To identify the potential role of Zeb1 in remodeling the tumor immune microenvironment in breast cancer, we crossed the floxed Zeb1 allele homozygously into PyMT mice to generate PyMT; Zeb1 cKO (MMTV-Cre;PyMT; Zeb1 fl/fl ) mice. We found that the recruitment of M2-type tumor-associated macrophages (TAMs) was significantly reduced in tumors from PyMT; Zeb1 cKO mice, and their tumor suppressive effects were weakened. Mechanistically, Zeb1 played a crucial role in transcriptionally promoting the production of Cxcl1 in tumor cells. In turn, Cxcl1 activated the Cxcr2-Jak-Stat3 pathway to induce M2 polarization of TAMs in a paracrine manner, which eventually led to T-cell inactivation and impaired the antitumor immune response in breast cancer. Our results collectively revealed an important role of Zeb1 in remodeling the tumor microenvironment, suggesting a novel therapeutic intervention for the treatment of advanced breast cancer.
Zeb1, a key epithelial-mesenchymal transition (EMT) regulator, has recently been found to be involved in M2 macrophage polarization in the tumor immune microenvironment, thereby promoting tumor development. However, the underlying mechanism of Zeb1-induced M2 macrophage polarization remains largely unexplored. To identify the potential role of Zeb1 in remodeling the tumor immune microenvironment in breast cancer, we crossed the floxed Zeb1 allele homozygously into PyMT mice to generate PyMT;Zeb1cKO (MMTV-Cre;PyMT;Zeb1fl/fl ) mice. We found that the recruitment of M2-type tumor-associated macrophages (TAMs) was significantly reduced in tumors from PyMT;Zeb1cKO mice, and their tumor suppressive effects were weakened. Mechanistically, Zeb1 played a crucial role in transcriptionally promoting the production of Cxcl1 in tumor cells. In turn, Cxcl1 activated the Cxcr2-Jak-Stat3 pathway to induce M2 polarization of TAMs in a paracrine manner, which eventually led to T-cell inactivation and impaired the antitumor immune response in breast cancer. Our results collectively revealed an important role of Zeb1 in remodeling the tumor microenvironment, suggesting a novel therapeutic intervention for the treatment of advanced breast cancer.Zeb1, a key epithelial-mesenchymal transition (EMT) regulator, has recently been found to be involved in M2 macrophage polarization in the tumor immune microenvironment, thereby promoting tumor development. However, the underlying mechanism of Zeb1-induced M2 macrophage polarization remains largely unexplored. To identify the potential role of Zeb1 in remodeling the tumor immune microenvironment in breast cancer, we crossed the floxed Zeb1 allele homozygously into PyMT mice to generate PyMT;Zeb1cKO (MMTV-Cre;PyMT;Zeb1fl/fl ) mice. We found that the recruitment of M2-type tumor-associated macrophages (TAMs) was significantly reduced in tumors from PyMT;Zeb1cKO mice, and their tumor suppressive effects were weakened. Mechanistically, Zeb1 played a crucial role in transcriptionally promoting the production of Cxcl1 in tumor cells. In turn, Cxcl1 activated the Cxcr2-Jak-Stat3 pathway to induce M2 polarization of TAMs in a paracrine manner, which eventually led to T-cell inactivation and impaired the antitumor immune response in breast cancer. Our results collectively revealed an important role of Zeb1 in remodeling the tumor microenvironment, suggesting a novel therapeutic intervention for the treatment of advanced breast cancer.
Author Yang, Shuang
Zuo, Si-Yu
Shi, Yi
Ou, Yang
Feng, Meng-Dan
Cao, Li-Xia
Wang, Hang
Chen, Xiao
Li, Zhao-Xian
Shi, Jie
Guo, Min
Hu, Hua-Yu
Wang, Yan-Jing
Liu, Yu-Xin
Sun, Pei-Qing
Shuai, Qiu-Ying
Jiang, Hui-Min
Qi, Chun-Chun
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  surname: Shi
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  givenname: Pei-Qing
  surname: Sun
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  organization: Department of Cancer Biology, Wake Forest Baptist Comprehensive Cancer Center, Wake Forest Baptist Medical Center Winston-Salem, NC, USA
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  surname: Yang
  fullname: Yang, Shuang
  organization: Tianjin Key Laboratory of Tumor Microenvironment and Neurovascular Regulation, School of Medicine, Nankai University Tianjin, P. R. China
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Keywords Zeb1
M2 macrophage polarization
antitumor immune response
Breast cancer
Cxcl1
tumor immune microenvironment
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Snippet Zeb1, a key epithelial-mesenchymal transition (EMT) regulator, has recently been found to be involved in M2 macrophage polarization in the tumor immune...
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Title The Zeb1-Cxcl1 axis impairs the antitumor immune response by inducing M2 macrophage polarization in breast cancer
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