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

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 () and Yufang Shi ()
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Zhiyuan Zheng: Institutes for Translational Medicine of Soochow 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

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-26460-z

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