Diabetes mellitus related fibroblast activation as a premetastatic niche enhances lung metastasis

Distant metastasis is a major determinant of poor prognosis in cancer. Epidemiological data indicate that diabetes markedly increases lung metastasis (LM) in patients with gastric cancer (GC); however, the underlying mechanisms remain unclear. Here, we report that high glucose stimulates GC cells to secrete extracellular vesicles (EVs) that activate FAP+ fibroblasts in the lung to establish a premetastatic niche and enhance metastasis. Transcriptomic and proteomic analyses revealed that high glucose activates FOXM1, promoting CEP55 transcription and its incorporation into EVs. Circulating CEP55-EVs trigger CEP55-pFAK-FAP signaling in lung fibroblasts, driving their activation. This results in extracellular matrix remodeling by tenascin-C secretion and scaffold formation to facilitate GC cell colonization. Finally, we demonstrate that the antidiabetic drug glimepiride suppresses fibroblast activation and significantly reduces LM. These findings reveal a diabetes-driven mechanism of LM mediated by CEP55-EVs and suggest a potent therapeutic strategy to inhibit LM using conventional antidiabetic drugs