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

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.