Highlight
• Fibroblast-derived Spondin-2 (SPON2) is identified as a pivotal secreted factor mediating the transition from metaplasia to dysplasia in gastric epithelial cells.
• Single-cell RNA sequencing and proteomic analyses revealed SPON2 is highly upregulated and secreted selectively by metaplasia- and cancer-derived fibroblasts compared with normal fibroblasts.
• Spatial transcriptomics localized PDGFRA/SPON2 co-expressing fibroblasts adjacent to metaplastic gastric glands in patient tissues.
• SPON2 knockdown in cancer-associated fibroblasts blocked dysplastic induction, whereas recombinant SPON2 treatment promoted dysplastic marker expression and downregulated metaplastic markers in gastroid cultures.
• Dysplastic changes induced by SPON2 were reversible upon withdrawal of SPON2 stimulation, indicating a dynamic and targetable process.
