O-GalNAc Glycosylation Activates MBL-Mediated Complement and Coagulation Cascades to Drive Organotropic Metastasis

  • Adv Sci (Weinh). 2025 Jun 10:e04809. doi: 10.1002/advs.202504809.
Xinyu Chen  1 ,  Wei Bao  1 ,  Kaiyuan Liu  1 ,  Na Jing  1 ,  Genyu Du  1 ,  Luyao Jiang  1 ,  Qian You  1 ,  Yingchao Zhang  1 ,  Penghui Xu  1  2 ,  Chaping Cheng  1 ,  Nan Wang  1 ,  Xialian Xi  1 ,  Mingyue Wang  1 ,  Yiyun Liu  1 ,  Jinming Wang  1 ,  Huifang Zhao  1 ,  Shilei Zhang  3 ,  Dinglan Wu  4 ,  Chi-Fai Ng  5 ,  Jiahua Pan  6 ,  Wei Xue  6 ,  Wei-Qiang Gao  1  2 ,  Pengcheng Zhang  7 ,  Kai Zhang  1 ,  Helen He Zhu  1
Affiliations
  • 1. 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.
  • 2. Med-X research Institute, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200030, China.
  • 3. Department of Pathology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China.
  • 4. Department of Surgery, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, 999077, China.
  • 5. S.H. Ho Urology Centre, Department of Surgery, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, 999077, China.
  • 6. Department of Urology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China.
  • 7. School of Biomedical Engineering, Shanghai Tech University, Shanghai, 201210, China.
PMID: 40492591 DOI: 10.1002/advs.202504809
Abstract

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.

Keywords
O‐GalNAc glycosylation; complement; glant9; liver metastasis; mannose binding lectin (MBL); neuroendocrine prostate cancer.
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