Abstract 282: SFRP4+ cancer associated fibroblasts activate epithelial to mesenchymal transitions in malignant cells and dictate adverse clinical outcomes in stomach cancer

Abstract Cancer-associated fibroblasts (CAFs), a pivotal component in the tumor microenvironment (TME) of gastric cancer (GC), play a crucial role in tumor progression and resistance to treatment. In this study, we performed analyses to build a comprehensive cellular landscape of fibroblasts in GC EMT using three single-cell RNA cohorts including ours (GSE183904, GSE134520 and GSE167297). We observed distinct fibroblast subtypes (CXCL14+/POSTN+, CXCL14+/APOE+, SFRP4+, and SFRP2+ fibroblasts). Among the subtypes, we observed that SFRP4+ fibroblasts sharing cellular origins with normal tissue-residing SFRP2+ myofibroblasts. Notably, SFRP4+ fibroblasts showed a regional prediction for tumor and deep tumor layers compared to normal and superficial tumor layers, respectively. To further understand the role of these fibroblasts, we employed spatial transcriptome data. Spatially resolving the cellular interactions within the TME, the adjacency of SFRP4+ CAFs to malignant cells undergoing epithelial-to-mesenchymal transition (EMT), was observed. Ligand-receptor analyses demonstrated SFRP4+CAFs regulate key genes of EMT in malignant cells (TGFBI, COL1A1, SPARC, COL3A1, COL1A2, and BGN). The regulatory roles of SFRP4+ CAFs in driving the epithelial-mesenchymal transition (EMT) of malignant cells were further validated in vitro. Clinical relevance was also demonstrated with the correlation between the abundance of SFRP4+ CAF and clinical outcomes, i. e. , high SFRP4+CAF abundance was consistently associated with shorter survival of GC patients across cohorts. Thus, we present SFRP4+ CAFs as major fibroblast subtypes in GC TME. Spatial cellular architectures and in vitro evidence support that SFRP4+fibroblasts activate the EMT of malignant cells along with their association with patient prognosis. 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. Citation Format: Seungho Lee, Austin Cho, Hyoung-Il Kim, Hoon Hur, Jae-Ho Cheong, Tae-Min Kim. SFRP4+ cancer associated fibroblasts activate epithelial to mesenchymal transitions in malignant cells and dictate adverse clinical outcomes in stomach cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 282.