Glycosylated Extracellular Vesicles Orchestrate a Gastric Cancer-Adipocytes Metabolic Interplay
Emerging evidence demonstrated that tumor cells and adipocytes engage in a dynamic interplay that drives cancer progression, contributing to systemic metabolic dysfunctions. Extracellular vesicles (EVs) have emerged as essential mediators in this tumor cell-adipocyte crosstalk. However, the role of EV glycosylation in this process remains largely unknown. Here, we uncover a pivotal role for glycosylation in driving a bidirectional metabolic reprogramming between tumor-associated adipocytes and gastric cancer cells. We demonstrate that gastric cancer cell-derived EVs displaying the tumor-associated glycan antigen sialyl-Tn can induce white-into-beige line adipocyte transdifferentiation, with increased lipolysis and increased release of glycerol and fatty acids. As a feedback mechanism, we observed reprogramming of gastric cancer cells' metabolism towards fatty acid oxidation, increased mitochondrial and endosomal biogenesis, and altered phenotypic features, especially tumor cells bearing aberrant glycosylation. STn antigen, a short O-glycan highly expressed in gastric cancer, has been associated with enhanced tumor aggressiveness, metastasis, and poor clinical outcomes. Collectively, our findings reveal a key role for aberrant glycosylation as a driver of tumor-associated adipocytes' metabolic reprogramming to sustain gastric cancer cells' energy needs.
Emerging evidence demonstrated that tumor cells and adipocytes engage in a dynamic interplay that drives cancer progression, contributing to systemic metabolic dysfunctions. Extracellular vesicles (EVs) have emerged as essential mediators in this tumor cell-adipocyte crosstalk. However, the role of EV glycosylation in this process remains largely unknown. Here, we uncover a pivotal role for glycosylation in driving a bidirectional metabolic reprogramming between tumor-associated adipocytes and gastric cancer cells. We demonstrate that gastric cancer cell-derived EVs displaying the tumor-associated glycan antigen sialyl-Tn can induce white-into-beige line adipocyte transdifferentiation, with increased lipolysis and increased release of glycerol and fatty acids. As a feedback mechanism, we observed reprogramming of gastric cancer cells' metabolism towards fatty acid oxidation, increased mitochondrial and endosomal biogenesis, and altered phenotypic features, especially tumor cells bearing aberrant glycosylation. STn antigen, a short O-glycan highly expressed in gastric cancer, has been associated with enhanced tumor aggressiveness, metastasis, and poor clinical outcomes. Collectively, our findings reveal a key role for aberrant glycosylation as a driver of tumor-associated adipocytes' metabolic reprogramming to sustain gastric cancer cells' energy needs.
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