SFRP4+ cancer associated fibroblasts activate epithelial-to-mesenchymal transitions in malignant cells and dictate adverse clinical outcomes in stomach cancer

Cancer-associated fibroblasts (CAF) in tumor microenvironment (TME) are considered fundamental in tumor progression and treatment resistance of gastric cancers (GC). Here, comprehensive cellular landscape of fibroblasts in GC TME were built based on three single-cell RNA sequencing dataset leading to a discovery of distinct fibroblast subtypes. Among the subtypes (CXCL14+/POSTN+, CXCL14+/APOE+, SFRP2+, and SFRP4+ fibroblasts), we observed that SFRP4+ fibroblasts sharing cellular origins with normal tissue-residing SFRP2+ myofibroblasts, exhibited the expression of active CAF markers such as ACTA2, TAGLN, POSTN, FAP and a regional prediction for tumor and deep tumor layers compared to normal and superficial tumor layers, respectively. Spatial transcriptome data delineated cellular interactions between TME cells highlighting the cellular adjacency of SFRP4+ CAFs with malignant cells showing epithelial-to-mesenchymal transition (EMT). Ligand-target analyses further demonstrated SFRP4+CAFs regulate key EMT genes of malignant cells such as TGFBI, COL1A1, SPARC, COL3A1, COL1A2, and BGN. The regulatory roles of SFRP4+ CAFs in driving the EMT of malignant cells were validated in vitro. Clinical relevance was also demonstrated where patients with high SFRP4+CAF abundance showed shorter survival consistently across cohorts. This study advances our understanding into the mechanistic roles of SFRP4+ fibroblasts in GC pathogenesis and progression, paving the way for potential targeted therapeutic strategies.