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ResearchIn-Press PreviewCell biologyOncology Open Access | 10.1172/JCI183544

5-HT orchestrates Histone Serotonylation and Citrullination to Drive Neutrophil Extracellular Traps and Liver Metastasis

Kaiyuan Liu,1 Yingchao Zhang,1 Genyu Du,1 Xinyu Chen,1 Lingling Xiao,2 Luyao Jiang,1 Na Jing,1 Penghui Xu,3 Chaoxian Zhao,1 Yiyun Liu,1 Huifang Zhao,1 Yujiao Sun,1 Jinming Wang,1 Chaping Cheng,1 Deng Wang,3 Jiahua Pan,1 Wei Xue,1 Pengcheng Zhang,4 Zhi-Gang Zhang,1 Wei-Qiang Gao,1 Shu-Heng Jiang,1 Kai Zhang,1 and Helen He Zhu1

1State Key Laboratory of Systems Medicine for Cancer, Renji-Med-X Stem Cell , Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China

2epartment of Emergency Medicine, Shanghai Seventh People’s Hospital, Seventh People’s Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, China

3Med-X Research Institute, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China

4School of Biomedical Engineering, Shanghai Tech University, Shanghai, China

Find articles by Liu, K. in: JCI | PubMed | Google Scholar

1State Key Laboratory of Systems Medicine for Cancer, Renji-Med-X Stem Cell , Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China

2epartment of Emergency Medicine, Shanghai Seventh People’s Hospital, Seventh People’s Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, China

3Med-X Research Institute, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China

4School of Biomedical Engineering, Shanghai Tech University, Shanghai, China

Find articles by Zhang, Y. in: JCI | PubMed | Google Scholar

1State Key Laboratory of Systems Medicine for Cancer, Renji-Med-X Stem Cell , Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China

2epartment of Emergency Medicine, Shanghai Seventh People’s Hospital, Seventh People’s Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, China

3Med-X Research Institute, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China

4School of Biomedical Engineering, Shanghai Tech University, Shanghai, China

Find articles by Du, G. in: JCI | PubMed | Google Scholar

1State Key Laboratory of Systems Medicine for Cancer, Renji-Med-X Stem Cell , Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China

2epartment of Emergency Medicine, Shanghai Seventh People’s Hospital, Seventh People’s Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, China

3Med-X Research Institute, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China

4School of Biomedical Engineering, Shanghai Tech University, Shanghai, China

Find articles by Chen, X. in: JCI | PubMed | Google Scholar

1State Key Laboratory of Systems Medicine for Cancer, Renji-Med-X Stem Cell , Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China

2epartment of Emergency Medicine, Shanghai Seventh People’s Hospital, Seventh People’s Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, China

3Med-X Research Institute, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China

4School of Biomedical Engineering, Shanghai Tech University, Shanghai, China

Find articles by Xiao, L. in: JCI | PubMed | Google Scholar

1State Key Laboratory of Systems Medicine for Cancer, Renji-Med-X Stem Cell , Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China

2epartment of Emergency Medicine, Shanghai Seventh People’s Hospital, Seventh People’s Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, China

3Med-X Research Institute, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China

4School of Biomedical Engineering, Shanghai Tech University, Shanghai, China

Find articles by Jiang, L. in: JCI | PubMed | Google Scholar

1State Key Laboratory of Systems Medicine for Cancer, Renji-Med-X Stem Cell , Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China

2epartment of Emergency Medicine, Shanghai Seventh People’s Hospital, Seventh People’s Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, China

3Med-X Research Institute, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China

4School of Biomedical Engineering, Shanghai Tech University, Shanghai, China

Find articles by Jing, N. in: JCI | PubMed | Google Scholar

1State Key Laboratory of Systems Medicine for Cancer, Renji-Med-X Stem Cell , Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China

2epartment of Emergency Medicine, Shanghai Seventh People’s Hospital, Seventh People’s Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, China

3Med-X Research Institute, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China

4School of Biomedical Engineering, Shanghai Tech University, Shanghai, China

Find articles by Xu, P. in: JCI | PubMed | Google Scholar

1State Key Laboratory of Systems Medicine for Cancer, Renji-Med-X Stem Cell , Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China

2epartment of Emergency Medicine, Shanghai Seventh People’s Hospital, Seventh People’s Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, China

3Med-X Research Institute, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China

4School of Biomedical Engineering, Shanghai Tech University, Shanghai, China

Find articles by Zhao, C. in: JCI | PubMed | Google Scholar

1State Key Laboratory of Systems Medicine for Cancer, Renji-Med-X Stem Cell , Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China

2epartment of Emergency Medicine, Shanghai Seventh People’s Hospital, Seventh People’s Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, China

3Med-X Research Institute, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China

4School of Biomedical Engineering, Shanghai Tech University, Shanghai, China

Find articles by Liu, Y. in: JCI | PubMed | Google Scholar

1State Key Laboratory of Systems Medicine for Cancer, Renji-Med-X Stem Cell , Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China

2epartment of Emergency Medicine, Shanghai Seventh People’s Hospital, Seventh People’s Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, China

3Med-X Research Institute, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China

4School of Biomedical Engineering, Shanghai Tech University, Shanghai, China

Find articles by Zhao, H. in: JCI | PubMed | Google Scholar

1State Key Laboratory of Systems Medicine for Cancer, Renji-Med-X Stem Cell , Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China

2epartment of Emergency Medicine, Shanghai Seventh People’s Hospital, Seventh People’s Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, China

3Med-X Research Institute, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China

4School of Biomedical Engineering, Shanghai Tech University, Shanghai, China

Find articles by Sun, Y. in: JCI | PubMed | Google Scholar

1State Key Laboratory of Systems Medicine for Cancer, Renji-Med-X Stem Cell , Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China

2epartment of Emergency Medicine, Shanghai Seventh People’s Hospital, Seventh People’s Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, China

3Med-X Research Institute, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China

4School of Biomedical Engineering, Shanghai Tech University, Shanghai, China

Find articles by Wang, J. in: JCI | PubMed | Google Scholar |

1State Key Laboratory of Systems Medicine for Cancer, Renji-Med-X Stem Cell , Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China

2epartment of Emergency Medicine, Shanghai Seventh People’s Hospital, Seventh People’s Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, China

3Med-X Research Institute, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China

4School of Biomedical Engineering, Shanghai Tech University, Shanghai, China

Find articles by Cheng, C. in: JCI | PubMed | Google Scholar

1State Key Laboratory of Systems Medicine for Cancer, Renji-Med-X Stem Cell , Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China

2epartment of Emergency Medicine, Shanghai Seventh People’s Hospital, Seventh People’s Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, China

3Med-X Research Institute, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China

4School of Biomedical Engineering, Shanghai Tech University, Shanghai, China

Find articles by Wang, D. in: JCI | PubMed | Google Scholar

1State Key Laboratory of Systems Medicine for Cancer, Renji-Med-X Stem Cell , Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China

2epartment of Emergency Medicine, Shanghai Seventh People’s Hospital, Seventh People’s Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, China

3Med-X Research Institute, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China

4School of Biomedical Engineering, Shanghai Tech University, Shanghai, China

Find articles by Pan, J. in: JCI | PubMed | Google Scholar

1State Key Laboratory of Systems Medicine for Cancer, Renji-Med-X Stem Cell , Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China

2epartment of Emergency Medicine, Shanghai Seventh People’s Hospital, Seventh People’s Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, China

3Med-X Research Institute, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China

4School of Biomedical Engineering, Shanghai Tech University, Shanghai, China

Find articles by Xue, W. in: JCI | PubMed | Google Scholar

1State Key Laboratory of Systems Medicine for Cancer, Renji-Med-X Stem Cell , Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China

2epartment of Emergency Medicine, Shanghai Seventh People’s Hospital, Seventh People’s Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, China

3Med-X Research Institute, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China

4School of Biomedical Engineering, Shanghai Tech University, Shanghai, China

Find articles by Zhang, P. in: JCI | PubMed | Google Scholar

1State Key Laboratory of Systems Medicine for Cancer, Renji-Med-X Stem Cell , Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China

2epartment of Emergency Medicine, Shanghai Seventh People’s Hospital, Seventh People’s Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, China

3Med-X Research Institute, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China

4School of Biomedical Engineering, Shanghai Tech University, Shanghai, China

Find articles by Zhang, Z. in: JCI | PubMed | Google Scholar |

1State Key Laboratory of Systems Medicine for Cancer, Renji-Med-X Stem Cell , Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China

2epartment of Emergency Medicine, Shanghai Seventh People’s Hospital, Seventh People’s Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, China

3Med-X Research Institute, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China

4School of Biomedical Engineering, Shanghai Tech University, Shanghai, China

Find articles by Gao, W. in: JCI | PubMed | Google Scholar

1State Key Laboratory of Systems Medicine for Cancer, Renji-Med-X Stem Cell , Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China

2epartment of Emergency Medicine, Shanghai Seventh People’s Hospital, Seventh People’s Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, China

3Med-X Research Institute, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China

4School of Biomedical Engineering, Shanghai Tech University, Shanghai, China

Find articles by Jiang, S. in: JCI | PubMed | Google Scholar

1State Key Laboratory of Systems Medicine for Cancer, Renji-Med-X Stem Cell , Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China

2epartment of Emergency Medicine, Shanghai Seventh People’s Hospital, Seventh People’s Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, China

3Med-X Research Institute, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China

4School of Biomedical Engineering, Shanghai Tech University, Shanghai, China

Find articles by Zhang, K. in: JCI | PubMed | Google Scholar

1State Key Laboratory of Systems Medicine for Cancer, Renji-Med-X Stem Cell , Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China

2epartment of Emergency Medicine, Shanghai Seventh People’s Hospital, Seventh People’s Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, China

3Med-X Research Institute, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China

4School of Biomedical Engineering, Shanghai Tech University, Shanghai, China

Find articles by Zhu, H. in: JCI | PubMed | Google Scholar

Published February 4, 2025 - More info

J Clin Invest. https://doi.org/10.1172/JCI183544.
Copyright © 2025, Liu et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published February 4, 2025 - Version history
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Abstract

Serotonin (5-HT) is a neurotransmitter that has been linked to tumorigenesis. Whether and how 5-HT modulates cells in the microenvironment to regulate tumor metastasis remains to be largely unknown. Here, we demonstrate that 5-HT is secreted by neuroendocrine prostate cancer (NEPC) cells to communicate with neutrophils and to induce neutrophil extracellular traps (NETs) in the liver, which in turn facilitates the recruitment of disseminated cancer cells and promotes liver metastasis. 5-HT induces histone serotonylation (H3Q5ser) and orchestrates histone citrullination (H3cit) in neutrophils to trigger chromatin decondensation and facilitate the formation of NETs. Interestingly, we uncover in this process a reciprocally reinforcing effect between H3Q5ser and H3cit and a crosstalk between the respective writers TGM2 and PAD4. Genetic ablation or pharmacological targeting of TGM2, or inhibiting 5-HT transporter (SERT) with the FDA-approved antidepressant drug fluoxetine reduces H3Q5ser and H3cit modifications, suppresses NETs formation, and effectively inhibits NEPC, small cell lung cancer, and thyroid medullary cancer liver metastasis. Collectively, the 5-HT-triggered NETs production highlights a new targetable neurotransmitter-immune axis in driving liver metastasis of neuroendocrine cancers.

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