Liu Kaiyuan, Zhang Yingchao, Du Genyu, Chen Xinyu, Xiao Lingling, Jiang Luyao, Jing Na, Xu Penghui, Zhao Chaoxian, Liu Yiyun, Zhao Huifang, Sun Yujiao, Wang Jinming, Cheng Chaping, Wang Deng, Pan Jiahua, Xue Wei, Zhang Pengcheng, Zhang Zhi-Gang, Gao Wei-Qiang, Jiang Shu-Heng, Zhang Kai, Zhu Helen He
State Key Laboratory of Systems Medicine for Cancer, Renji-Med-X Stem Cell Research Center, Department of Urology, Renji Hospital, Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Department of Emergency Medicine, Shanghai Seventh People's Hospital, Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, China.
J Clin Invest. 2025 Feb 4;135(8). doi: 10.1172/JCI183544. eCollection 2025 Apr 15.
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 is largely unknown. Here, we demonstrate that 5-HT was secreted by neuroendocrine prostate cancer (NEPC) cells to communicate with neutrophils and to induce the formation of neutrophil extracellular traps (NETs) in the liver, which in turn facilitated the recruitment of disseminated cancer cells and promoted liver metastasis. 5-HT induced histone serotonylation (H3Q5ser) and orchestrated histone citrullination (H3cit) in neutrophils to trigger chromatin decondensation and facilitate the formation of NETs. Interestingly, we uncovered in this process a reciprocally reinforcing effect between H3Q5ser and H3cit and a crosstalk between the respective writers enzyme transglutaminase 2 (TGM2) and peptidylarginine deiminase 4 (PAD4). Genetic ablation or pharmacological targeting of TGM2, or inhibition of the 5-HT transporter (SERT) with the FDA-approved antidepressant drug fluoxetine reduced H3Q5ser and H3cit modifications, suppressed NET formation, and effectively inhibited NEPC, small-cell lung cancer, and thyroid medullary cancer liver metastasis. Collectively, the 5-HT-triggered production of NETs highlights a targetable neurotransmitter/immune axis that drives liver metastasis of NE cancers.
血清素（5-羟色胺，5-HT）是一种与肿瘤发生相关的神经递质。5-HT是否以及如何调节微环境中的细胞以调控肿瘤转移，目前尚不清楚。在此，我们证明神经内分泌前列腺癌（NEPC）细胞分泌5-HT，与中性粒细胞进行通信，并诱导肝脏中中性粒细胞胞外诱捕网（NETs）的形成，这反过来又促进了播散癌细胞的募集并促进肝转移。5-HT诱导中性粒细胞中的组蛋白血清素化（H3Q5ser）并协调组蛋白瓜氨酸化（H3cit），以触发染色质去凝聚并促进NETs的形成。有趣的是，我们在这个过程中发现了H3Q5ser和H3cit之间的相互增强作用，以及各自的写入酶转谷氨酰胺酶2（TGM2）和肽基精氨酸脱亚氨酶4（PAD4）之间的串扰。对TGM2进行基因敲除或药物靶向，或使用FDA批准的抗抑郁药氟西汀抑制5-HT转运体（SERT），可减少H3Q5ser和H3cit修饰，抑制NETs形成，并有效抑制NEPC、小细胞肺癌和甲状腺髓样癌的肝转移。总的来说，5-HT触发的NETs产生突出了一个可靶向的神经递质/免疫轴，该轴驱动NE癌症的肝转移。
