2. Academic Validation
  3. Neutrophil extracellular traps mediate TLR9/Merlin axis to resist ferroptosis and promote triple negative breast cancer progression

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

  • Apoptosis. 2023 Jun 27. doi: 10.1007/s10495-023-01866-w.
Linli Yao # 1,  Xiaonan Sheng # 2,  Xinrui Dong # 2,  Weihang Zhou 2,  Ye Li 2,  Xueyun Ma 3,  Yonggang Song 4,  Huijuan Dai 5,  Yueyao Du 6
Affiliations

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.
  • 2 Department of Breast Surgery, School of Medicine, Renji Hospital, Shanghai Jiaotong University, Shanghai, People's Republic of China.
  • 3 Institute of Biomedical Sciences, East China Normal University, Shanghai, People's Republic of China.
  • 4 The Affiliated Huaian Hospital of Xuzhou Medical University, Huaian, People's Republic of China. [email protected].
  • 5 Department of Breast Surgery, School of Medicine, Renji Hospital, Shanghai Jiaotong University, Shanghai, People's Republic of China. [email protected].
  • 6 Department of Breast Surgery, School of Medicine, Renji Hospital, Shanghai Jiaotong University, Shanghai, People's Republic of China. [email protected].
  • # Contributed equally.
PMID: 37368176 DOI: 10.1007/s10495-023-01866-w
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.

Keywords

Ferroptosis; Neutrophil extracellular traps; TLR9/Merlin signaling; Triple negative breast cancer.

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