Nicotine promotes breast cancer metastasis by stimulating N2 neutrophils and generating pre-metastatic niche in lung

Abhishek Tyagi, Sambad Sharma, Kerui Wu, Shih-Ying Wu, Fei Xing, Yin Liu, Dan Zhao, Ravindra Pramod Deshpande, Ralph B. D’Agostino, Kounosuke Watabe

Research output: Contribution to journalArticlepeer-review

168 Scopus citations

Abstract

Smoking has a profound impact on tumor immunity, and nicotine, which is the major addictive component of smoke, is known to promote tumor progression despite being a non-carcinogen. In this study, we demonstrate that chronic exposure of nicotine plays a critical role in the formation of pre-metastatic niche within the lungs by recruiting pro-tumor N2-neutrophils. This pre-metastatic niche promotes the release of STAT3-activated lipocalin 2 (LCN2), a secretory glycoprotein from the N2-neutrophils, and induces mesenchymal-epithelial transition of tumor cells thereby facilitating colonization and metastatic outgrowth. Elevated levels of serum and urine LCN2 is elevated in early-stage breast cancer patients and cancer-free females with smoking history, suggesting that LCN2 serve as a promising prognostic biomarker for predicting increased risk of metastatic disease in female smoker(s). Moreover, natural compound, salidroside effectively abrogates nicotine-induced neutrophil polarization and consequently reduced lung metastasis of hormone receptor-negative breast cancer cells. Our findings suggest a pro-metastatic role of nicotine-induced N2-neutrophils for cancer cell colonization in the lungs and illuminate the therapeutic use of salidroside to enhance the anti-tumor activity of neutrophils in breast cancer patients.
Original languageAmerican English
Article number474
Pages (from-to)474
JournalNature Communications
Volume12
Issue number1
DOIs
StatePublished - 2021
Externally publishedYes

Keywords

  • Animals
  • Biomarkers, Tumor
  • Breast Neoplasms/chemically induced
  • Cell Line, Tumor
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Lipocalin-2/metabolism
  • Lung Neoplasms/metabolism
  • Lung/metabolism
  • Mice
  • Neoplasm Metastasis/genetics
  • Neutrophil Infiltration/drug effects
  • Neutrophils/metabolism
  • Nicotine/adverse effects
  • STAT3 Transcription Factor/genetics
  • Smoking

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