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Lung mesenchymal stromal cells influenced by Th2 cytokines mobilize neutrophils and facilitate metastasis by producing complement C3

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  • Zhiyuan Zheng

    (Institutes for Translational Medicine of Soochow University
    Zhejiang University)

  • Ya-nan Li

    (Institutes for Translational Medicine of Soochow University)

  • Shanfen Jia

    (Institutes for Translational Medicine of Soochow University)

  • Mengting Zhu

    (Institutes for Translational Medicine of Soochow University)

  • Lijuan Cao

    (Institutes for Translational Medicine of Soochow University)

  • Min Tao

    (The First Affiliated Hospital of Soochow University/The First People’s Hospital of Suzhou)

  • Jingting Jiang

    (Institutes for Translational Medicine of Soochow University)

  • Shenghua Zhan

    (The First Affiliated Hospital of Soochow University/The First People’s Hospital of Suzhou)

  • Yongjing Chen

    (Institutes for Translational Medicine of Soochow University)

  • Ping-Jin Gao

    (Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences)

  • Weiguo Hu

    (Fudan University)

  • Ying Wang

    (Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences)

  • Changshun Shao

    (Institutes for Translational Medicine of Soochow University)

  • Yufang Shi

    (Institutes for Translational Medicine of Soochow University
    The First Affiliated Hospital of Soochow University/The First People’s Hospital of Suzhou
    Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences)

Abstract

Pre-metastatic niche formation is critical for the colonization of disseminated cancer cells in distant organs. Here we find that lung mesenchymal stromal cells (LMSCs) at pre-metastatic stage possess potent metastasis-promoting activity. RNA-seq reveals an upregulation of complement 3 (C3) in those LMSCs. C3 is found to promote neutrophil recruitment and the formation of neutrophil extracellular traps (NETs), which facilitate cancer cell metastasis to the lungs. C3 expression in LMSCs is induced and sustained by Th2 cytokines in a STAT6-dependent manner. LMSCs-driven lung metastasis is abolished in Th1-skewing Stat6-deficient mice. Blockade of IL-4 by antibody also attenuates LMSCs-driven cancer metastasis to the lungs. Consistently, metastasis is greatly enhanced in Th2-skewing T-bet-deficient mice or in nude mice adoptively transferred with T-bet-deficient T cells. Increased C3 levels are also detected in breast cancer patients. Our results suggest that targeting the Th2-STAT6-C3-NETs cascade may reduce breast cancer metastasis to the lungs.

Suggested Citation

  • Zhiyuan Zheng & Ya-nan Li & Shanfen Jia & Mengting Zhu & Lijuan Cao & Min Tao & Jingting Jiang & Shenghua Zhan & Yongjing Chen & Ping-Jin Gao & Weiguo Hu & Ying Wang & Changshun Shao & Yufang Shi, 2021. "Lung mesenchymal stromal cells influenced by Th2 cytokines mobilize neutrophils and facilitate metastasis by producing complement C3," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-26460-z
    DOI: 10.1038/s41467-021-26460-z
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