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Neutrophil extracellular traps mediate TLR9/Merlin axis to resist ferroptosis and promote triple negative breast cancer progression

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Abstract

Neutrophil and neutrophil extracellular traps (NETs) were reported to be associated with tumor development, but the exact role and concrete mechanisms are still poorly understood, especially in triple negative breast cancer (TNBC). In this study, our results exhibited that NETs formation in TNBC tissues was higher than that in non-TNBC tissues, and NETs formation was distinctly correlated with tumor size, ki67 level and lymph node metastasis in TNBC patients. Subsequent in vivo experiments demonstrated that NETs inhibition could suppress TNBC tumor growth and lung metastasis. Further in vitro experiments uncovered that oncogenic function of NETs on TNBC cells were possibly dependent on TLR9 expression. We also found that neutrophils from peripheral blood of TNBC patients with postoperative fever were prone to form NETs and could enhance the proliferation and invasion of TNBC cells. Mechanistically, we revealed that NETs could interact with TLR9 to decrease Merlin phosphorylation which contributed to TNBC cell ferroptosis resistance. Our work provides a novel insight into the mechanism of NETs promoting TNBC progression and blocking the key modulator of NETs might be a promising therapeutic strategy in TNBC.

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The data are available within the Article, Supplementary Information, or available from the authors upon request. Source data are provided with this paper.

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Acknowledgements

The patients are gratefully acknowledged for their participation in this study.

Funding

This work was supported by the National Natural Science Foundation of China (No. 82002777), Multidisciplinary Cross Research Foundation of Shanghai Jiao Tong University (No. YG2019QNA26), Shanghai Sailing Program (22YF1424500).

Author information

Author notes

  1. Linli Yao, **aonan Sheng and **nrui Dong have contributed equally to this work.

Authors and Affiliations

  1. State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, School of Medicine, Ren Ji Hospital, Shanghai Jiao Tong University, Shanghai, People’s Republic of China

    Linli Yao

  2. Department of Breast Surgery, School of Medicine, Renji Hospital, Shanghai Jiaotong University, Shanghai, People’s Republic of China

    **aonan Sheng, **nrui Dong, Weihang Zhou, Ye Li, Huijuan Dai & Yueyao Du

  3. The Affiliated Huaian Hospital of Xuzhou Medical University, Huaian, People’s Republic of China

    Yonggang Song

  4. Institute of Biomedical Sciences, East China Normal University, Shanghai, People’s Republic of China

    Xueyun Ma

Authors
  1. Linli Yao
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  2. **aonan Sheng
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  3. **nrui Dong
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  4. Weihang Zhou
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  5. Ye Li
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  7. Yonggang Song
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  8. Huijuan Dai
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  9. Yueyao Du
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Contributions

HD, YD, YS conceived of the study and participated in its design and coordination. LY, XD, XS, YL and WZ performed molecular biological experiments. HD, XS, XD, YD collected samples. LY, HD, YS contributed to data acquisition and analysis. XS, XM, YS performed the statistical analyses for all the data. HD, XS drafted the manuscript. LY, YD, YS, HD, XM revised the manuscript. All authors contributed to the article and approved the submitted version.

Corresponding authors

Correspondence to Yonggang Song, Huijuan Dai or Yueyao Du.

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Conflict of interest

The authors declare that they have no competing interests with the contents of this article.

Ethical approval

The studies involving human participants were reviewed and approved by The Affiliated Huaian Hospital of Xuzhou Medical University. The patients/participants provided their written informed consent to participate in this study.

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Yao, L., Sheng, X., Dong, X. et al. Neutrophil extracellular traps mediate TLR9/Merlin axis to resist ferroptosis and promote triple negative breast cancer progression. Apoptosis 28, 1484–1495 (2023). https://doi.org/10.1007/s10495-023-01866-w

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