Unveiling the role of gastric cancer-associated mesenchymal stem cells and neutrophil extracellular traps through multi-omics analysis.

[BACKGROUND] Gastric cancer (GC) is a highly aggressive malignancy with a poor prognosis, closely linked to the tumor microenvironment (TME). Emerging evidence highlights the critical role of gastric cancer-associated mesenchymal stem cells (GC-MSCs) in recruiting neutrophils and facilitating neutrophil extracellular traps (NETs) formation, thereby remodeling the tumor microenvironment (TME) and promoting tumor progression, immune modulation, and metastasis.

[METHODS] This study integrated single-cell RNA sequencing (scRNA-seq), Mendelian randomization (MR), and functional enrichment analyses to uncover the molecular underpinnings of GC. Transcriptomic data from public databases, including TCGA and GEO, were analyzed to explore cellular heterogeneity and the influence of NETs within the TME. MR analysis was conducted to establish causal relationships between key NET-related genes and GC. We integrated scRNA-seq, MR, and functional enrichment analyses to systematically dissect the roles of GC-MSCs and NETs in reshaping the tumor microenvironment.

[RESULTS] scRNA-seq identified 12 distinct cell types in the TME, with significantly elevated NET scores associated with GC-MSCs in the disease group. Functional enrichment analyses revealed that NET-associated marker genes were enriched in pathways such as oxidative phosphorylation and cytoplasmic translation. MR analysis confirmed EIF1 and RPS12 as key genes with causal links to GC progression, demonstrating robust associations with immune cell infiltration and critical signaling pathways. Additionally, transcriptional regulation analysis identified motifs and transcription factors governing these genes, while GSEA highlighted their involvement in pathways such as ribosome biogenesis and focal adhesion.

[CONCLUSION] This study elucidates the intricate interplay between GC-MSCs, NETs, and the immune microenvironment, offering novel insights into GC pathogenesis and potential therapeutic targets. EIF1 and RPS12 emerge as promising candidates for precision medicine, with broader implications for NET-related cancer research.