Abstract A052: CA19-9 promotes liver metastasis of pancreatic cancer through E-selectin mediated seeding in mice

Abstract

Pancreatic ductal adenocarcinoma (PDAC) frequently metastasizes to the liver, resulting in poor patient survival. Elevated serum carbohydrate antigen 19-9 (CA19-9) is associated with poor prognosis and early postoperative recurrence. We previously demonstrated that CA19-9 promotes pancreatitis and pancreatic cancer in mice. However, whether CA19-9 actively promotes liver metastasis remains unclear. Using murine cells expressing human CA19-9, we investigated the mechanisms by which CA19-9 regulates liver metastasis and evaluated its potential as a therapeutic target. We generated syngeneic murine PDAC cells expressing CA19-9. Liver metastasis was evaluated using hemisplenic injection models in immunocompetent mice. Endothelial adhesion was assessed using TNF-α-stimulated HUVECs. Functional significance of the CA19-9/E-selectin axis was examined using E-selectin knockout mice and neutralizing antibodies against CA19-9 or E-selectin. RNA sequencing, immunoblotting, immunohistochemistry, and analysis of human PDAC tissue microarrays were performed to investigate downstream signaling pathways. CA19-9 expression significantly increased liver metastatic burden by increasing both metastatic number and size of metastatic lesions. In vitro, CA19-9 enhanced adhesion of both murine and human PDAC cells to TNF-α-stimulated endothelial cells. Neutralization of either CA19-9 or E-selectin significantly reduced endothelial adhesion. In vivo, genetic deletion of E-selectin or antibody-mediated blockade of either CA19-9 or E-selectin markedly suppressed early hepatic metastatic seeding. These findings indicate that CA19-9 promotes hepatic metastatic seeding through E-selectin-mediated endothelial interactions. Additionally, therapeutic administration of an anti-CA19-9 antibody after metastatic seeding significantly reduced liver metastatic burden, indicating that CA19-9 promotes metastatic outgrowth. Transcriptomic profiling revealed enrichment of the PI3K-AKT-mTOR signaling pathway in CA19-9-positive cells, which was supported by increased AKT phosphorylation in CA19-9-positive tumors. Anti-CA19-9 antibody treatment reduced AKT phosphorylation in metastatic lesions, indicating that CA19-9 promotes metastatic outgrowth through activation of AKT signaling. Importantly, analysis of human PDAC tissue microarrays showed a positive correlation between CA19-9 expression and AKT activation. Furthermore, elevated preoperative serum CA19-9 remained associated with significantly worse survival even among patients with stage IA PDAC, supporting a functional role for CA19-9 beyond simply reflecting tumor burden. Collectively, these findings show that CA19-9 promotes PDAC liver metastasis through E-selectin-dependent metastatic seeding and AKT-associated metastatic outgrowth, highlighting CA19-9 as a functional mediator of PDAC metastasis and a potential therapeutic target.Generative AI was used to assist with language editing of this abstract.