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G6PD activation in TNBC cells induces macrophage recruitment and M2 polarization to promote tumor progression

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Abstract

Glucose-6-phosphate dehydrogenase (G6PD) is involved in triple-negative breast cancer (TNBC) progression. Metabolic crosstalk between cancer cells and tumor-associated macrophages mediates tumor progression in TNBC. Molecular biological methods were applied to clarify the mechanism of the crosstalk between TNBC cells and M2 macrophages. In the present study, we verified that G6PD overexpression drives M2 macrophage polarization by directly combining with phospho-STAT1 and upregulating CCL2 and TGF-β1 secretion in TNBC cells. In turn, M2-like TAMs activated TNBC cells through IL-10 secretion, providing feedback to upregulate G6PD and promote TNBC cell migration and proliferation in vitro. Furthermore, we found that 6-AN (a specific inhibitor of G6PD) not only suppressed the cancer-driven polarization of macrophages toward the M2 phenotype but also inhibited the inherent M2 polarization of macrophages. Targeting the G6PD-regulated pentose phosphate pathway restrained TNBC progression and M2-type polarization of macrophages in vitro and in vivo.

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Data availability

The authors confirm that the data supporting the findings of this study are available within the article. The raw data are available from the corresponding author upon reasonable request. Figure 1D data analyzed in this study were obtained from the Gene Expression Omnibus (GEO) at GSE81032.

Abbreviations

TNBC:

Triple-negative breast cancer.

PPP:

Pentose phosphate pathway.

G6PD:

Glucose-6-phosphate dehydrogenase.

6-AN:

6-Aminonicotinamide.

TAMs:

Tumor-associated macrophages.

Mφ:

Macrophage.

ELISA:

Enzyme-linked Immunosorbent Assay.

CM:

Conditioned medium.

q-PCR:

Quantitative polymerase chain reaction.

MTT:

Thiazolyl blue.

IHC:

Immunohistochemistry.

H&E:

Hematoxylin and eosin.

DAPI:

4′,6-Diamidino-2-phenylindole.

CCL2:

Chemokine (C–C motif) ligand 2

TGF-β1:

Transforming growth factor beta 1

IL-10:

Interleukin-10

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Acknowledgements

We would like to thank Gang Zhao (Department of Pathology, Tianjin Cancer Hospital) and the breast surgery department of Peking Union Medical College Hospital for supplying breast cancer tissue sections, Miaomiao Sheng (Kunming University of Science and Technology) for providing breast cancer cell lines, and Xinying Wu (Animal Center of Nankai University) for technical support of in vivo imaging.

Funding

This study was partially funded by “State Key Laboratory of Medicinal Chemical Biology (NanKai University, No. 2019014)” to C W and “The Fundamental Research Funds for the Central Universities (Nankai University, #ZB19100128)” to C L.

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Authors and Affiliations

  1. State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, No.38 Tongyan Road, Jinnan District, Tianjin, 300350, People’s Republic of China

    Yin Li, Xiao Han, Zhoujun Lin & Chenggang Li

  2. Department of Immunology, Wu Lien-Teh Institute, Heilongjiang Provincial Key Laboratory for Infection and Immunity, Harbin Medical University & Heilongjiang Academy of Medical Science, No.157 Baojian Street, Nangang District, Harbin, 150086, People’s Republic of China

    Zhenkun Fu

  3. Department of Breast Surgery, Peking Union Medical College Hospital, No.1 Shuaifuyuan, Dongcheng District, Beijing, 100730, China

    Changjun Wang & Qiang Sun

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  1. Yin Li
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Contributions

Y L, X H and Z F designed, performed and analyzed the in vivo experiments. Y L, X H and Z F performed and analyzed G6PD knockdown experiments in vitro and in vivo. Y L, X H and Z L provided guidance on data processing and writing. C L, Y L, C W, Q S and Z F contributed to the study design, implementation and supervision of the study. Z L, Z F, C W, Q S and C L contributed to the study design, supervised the study, and reviewed the manuscript. Y L and C L wrote the manuscript. All authors had full access to the data and approved the final version of the manuscript.

Corresponding authors

Correspondence to Changjun Wang, Zhenkun Fu, Qiang Sun or Chenggang Li.

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Animal experiments were performed according to the Guidelines on Laboratory Animals of Nankai University and were approved by the Institute Research Ethics Committee at Nankai University (No: 2021-SYDWLL-000464). Human experiments were approved by the human experimentation committee, and informed consent was obtained from all subjects (No: NKUIRB2021105).

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Li, Y., Han, X., Lin, Z. et al. G6PD activation in TNBC cells induces macrophage recruitment and M2 polarization to promote tumor progression. Cell. Mol. Life Sci. 80, 165 (2023). https://doi.org/10.1007/s00018-023-04810-y

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