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 and Kounosuke Watabe ()
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Abhishek Tyagi: Department of Cancer Biology, Wake Forest Baptist Medical Center
Sambad Sharma: Department of Cancer Biology, Wake Forest Baptist Medical Center
Kerui Wu: Department of Cancer Biology, Wake Forest Baptist Medical Center
Shih-Ying Wu: Department of Cancer Biology, Wake Forest Baptist Medical Center
Fei Xing: Department of Cancer Biology, Wake Forest Baptist Medical Center
Yin Liu: Department of Cancer Biology, Wake Forest Baptist Medical Center
Dan Zhao: Department of Cancer Biology, Wake Forest Baptist Medical Center
Ravindra Pramod Deshpande: Department of Cancer Biology, Wake Forest Baptist Medical Center
Ralph B. D’Agostino: Biostatistics Core, Wake Forest Baptist Medical Center
Kounosuke Watabe: Department of Cancer Biology, Wake Forest Baptist Medical Center

Nature Communications, 2021, vol. 12, issue 1, 1-18

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-020-20733-9

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