Chen Xinyu, Bao Wei, Liu Kaiyuan, Jing Na, Du Genyu, Jiang Luyao, You Qian, Zhang Yingchao, Xu Penghui, Cheng Chaping, Wang Nan, Xi Xialian, Wang Mingyue, Liu Yiyun, Wang Jinming, Zhao Huifang, Zhang Shilei, Wu Dinglan, Ng Chi-Fai, Pan Jiahua, Xue Wei, Gao Wei-Qiang, Zhang Pengcheng, Zhang Kai, Zhu Helen He
State Key Laboratory of Systems Medicine for Cancer, Department of Urology, Ren Ji Hospital, Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China.
Med-X research Institute, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200030, China.
Adv Sci (Weinh). 2025 Aug;12(32):e04809. doi: 10.1002/advs.202504809. Epub 2025 Jun 10.
Liver metastasis is prevalent among patients with neuroendocrine prostate cancer (NEPC) and other types of neuroendocrine (NE) cancers, featuring with an aggressive clinical course and a dismal prognosis. However, the cellular and molecular mechanisms underlying liver-specific metastatic tropism in NE cancers remain poorly understood. Intriguingly, it is found that NEPC liver metastatic foci are frequently associated with thrombi. NEPC cells express an aberrantly elevated level of glycosyltransferase Galnt9. Notably, the Galnt9-mediated O-GalNAc glycosylation on the cell membrane of NE cancer cells, particularly on the adhesion molecule Annexin A2, activates the mannose-binding lectin (MBL) complement signaling in the liver. This cascade stimulates platelet activation and thrombus formation, ultimately facilitating hepatic metastasis of NEPC. Inhibition of O-GalNAc glycosylation or knockdown of Galnt9 demonstrates efficacy in restraining the liver metastasis of NEPC, small cell lung cancer (SCLC), and colorectal neuroendocrine cancer. These findings identify Galnt9-mediated O-GalNAc glycosylation as a targetable mechanism driving liver metastasis through activation of MBL complement and coagulation cascades across a broad spectrum of NE cancers.
肝转移在神经内分泌前列腺癌（NEPC）和其他类型的神经内分泌（NE）癌患者中很常见，其临床病程具有侵袭性，预后不良。然而，NE癌中肝脏特异性转移趋向性的细胞和分子机制仍知之甚少。有趣的是，发现NEPC肝转移灶常与血栓有关。NEPC细胞中糖基转移酶Galnt9的表达异常升高。值得注意的是，Galnt9介导的NE癌细胞膜上的O-GalNAc糖基化，特别是在粘附分子膜联蛋白A2上，激活了肝脏中的甘露糖结合凝集素（MBL）补体信号。这一级联反应刺激血小板活化和血栓形成，最终促进NEPC的肝转移。抑制O-GalNAc糖基化或敲低Galnt9在抑制NEPC、小细胞肺癌（SCLC）和结直肠神经内分泌癌的肝转移方面显示出疗效。这些发现表明，Galnt9介导的O-GalNAc糖基化是一种可靶向的机制，通过激活MBL补体和凝血级联反应，驱动广泛的NE癌发生肝转移。
