Role of Cancer-Associated Fibroblasts in Prognostic Stratification of Advanced-Stage Gastric Cancer through Interacting with Endothelial and Malignant Epithelial Cells [AGC RNA-seq]

Patients with advanced gastric cancers (AGCs) would experience poor prognosis, lacking investigation on comprehensive ecosystem profile and specific prognostic factors. Here, we conducted patient stratification based on unsupervised clustering of transcriptomic profile of 108 normal/tumor AGC pairs and integrated single-cell RNA transcriptome profile of 116 gastric cancer/normal samples, revealing the heterogeneity of AGC, which can be stratified into distinct AGC-related signature (AGCRS)-based patient groups with different prognosis. AGCRS scores are over-presented in cancer-associated fibroblasts (CAF) and increase in metastasis-enriched subtypes (e.g., myofibroblastic CAF). More prolific cell-cell communications were observed between CAF and metastasis-enriched epithelial/endothelial through collagen-related interactions. Experimentally, CAF conditional-medium can enhance the tube formation of endothelial cells and HOXC-AS2-related migration ability of gastric cancer cells. Particularly, HOX-AS2 can facilitate the nucleus translocation of YBX1 through direct binding in cytoplasm and induce the epithelial-mesenchymal transition. Our findings highlight the potential prognostic role of AGC heterogeneity induced by CAF-related communications.