Aggressive Gastric Cancer Overexpresses Trimmed N-Glycans and Exhibits Distinct Glycoproteome Signatures Predictive of Poor Prognosis

Gastric cancer poses a significant threat at advanced stages, with the identification of molecular signatures for prognosis and targeted treatment remaining crucial yet challenging. This study investigates the under-characterized gastric cancer glycocalyx, revealing glycan signatures linked to cancer aggressiveness through high-throughput N-glycome analysis. Our findings show that aggressive tumors with poorer prognoses are enriched with trimmed paucimannosidic N-glycans. Lectin immunoblotting confirmed the disease-specific nature of these glycans, showing increased expression with cancer progression. Furthermore, TCGA analysis of over 400 cases revealed a correlation between key glycosyltransferase expression, associated with paucimannose biosynthesis, and poor prognosis, providing a potential molecular basis for these observations. Paucimannose N-glycans were predominantly found in intracellular ribosomal proteins challenging classical links with the plasma membrane proteome, though notable membrane proteins like CEACAM6 and MMP9 were identified. MMP9 demonstrated limited expression in healthy tissues, increasing with disease stage and grade. Tumors expressing MMP9 and paucimannosidic glycans also exhibited the worst prognosis. This work advances our understanding of gastric cancer glycome, highlighting the clinical context for paucimannosidic N-glycans and its underlying glycoproteome, providing potential targets for more precise therapeutic approaches.