Distinct glycosyltransferase expression governs organ-specific survival in pancreatic cancer metastasis

Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal cancers, with over 83% of patients presenting metastases to vital organs such as the liver, lungs, and peritoneum. Although glycosylation has been established as a critical factor in PDAC development, little is known about the molecular underpinnings of organ-specific metastasis. In this study, we investigated the role of glycosyltransferases (GTs) in mediating PDAC metastatic organotropism. Through an unbiased transcriptomic screen, we identified distinct GT expression patterns in liver- and lung-tropic PDAC cells. Notably, GCNT3 and B3GNT3 were selectively upregulated in liver and lung-tropic cells, respectively. These mutually exclusive expression patterns were validated in human metastatic PDAC specimens, where GCNT3 was enriched in liver metastatic lesions and B3GNT3 in lung metastases. Proteomic profiling revealed that differential expression of these GTs is associated with epithelial-mesenchymal transition and glycoproteome remodeling in metastatic cells. Functional studies using in vitro assays, ex vivo organotypic cultures, and in vivo metastasis models demonstrated that loss of GCNT3 or B3GNT3 impairs the proliferation and survival of PDAC cells in their respective metastatic organ environments. Together, these findings uncover a glycosylation-based mechanism that facilitates organ-specific survival of metastatic PDAC cells and highlight glycosyltransferases as potential therapeutic targets for disrupting metastatic adaptation.