Glycosylated extracellular vesicles drive a metabolic interplay between gastric cancer cells and adipocytes

Aim: Tumor cells and extracellular vesicles (EVs) dynamically interact with adipocytes, contributing to tumor progression and systemic metabolic dysfunctions. While the role of glycosylation in this process remains unclear, glycans facilitate communication between tumors and their surrounding environment. Here, we aimed to elucidate the pivotal role of sialyl-Tn (STn), a tumor-associated glycan, in driving a bidirectional metabolic reprogramming between gastric cancer cells and adipocytes. Methods: EVs were isolated from gastric cancer cells with distinct glycosylation profiles by ultracentrifugation and characterized by transmission electron microscopy, nanoparticle tracking analysis, and western blotting. Flow cytometry was used to quantify EV uptake by adipocytes. EV-mediated adipocyte browning and lipolysis were measured by real-time quantitative polymerase chain reaction, glycerol and fatty acid release, perilipin immunofluorescence, and western blotting analysis of lipid synthesis and hydrolysis enzymes. The reciprocal effects of beige adipocytes on tumor cells were evaluated using fatty acid uptake assays, metabolomics, RNA sequencing, Seahorse metabolic flux, organelle number, proliferation, and migration assays. Results: STn-positive gastric cancer cells and EVs induced white-into-beige transdifferentiation. These cells exhibited an enhanced capacity to release glycerol and fatty acids, which were predominantly taken up by gastric cancer cells displaying STn. As a feedback mechanism, gastric cancer cells shift their metabolism towards fatty acid oxidation, concomitant with increased mitochondrial and endosomal biogenesis, and enhanced motility. Conclusion: Our findings reveal a key role for the tumor-associated glycan STn in metabolic reprogramming of adipocytes by tumor cells and EVs, opening new avenues for targeted therapies in cancer patients experiencing metabolic dysfunctions, such as cancer cachexia.