EGR4 Transcriptionally Upregulates GDF15 to Promote Gastric Cancer Metastasis

Gastric cancer (GC) metastasis remains a major cause of poor prognosis, yet its molecular drivers are poorly understood. Here, we integrated single-cell RNA sequencing (scRNA-seq) of primary tumors and matched metastatic lymph nodes from six GC patients to identify a metastatic epithelial subpopulation characterized by EGR4 overexpression. Kaplan-Meier analysis revealed that high EGR4 expression correlated with reduced survival in GC patients. Mechanistically, chromatin immunoprecipitation sequencing (ChIP-seq) and luciferase assays demonstrated that EGR4 directly binds to the GDF15 promoter, driving its transcriptional activation. Functional studies showed that EGR4 promote migration and metastasis via GDF15-mediated ErbB3/ErbB1 hetero-dimerization, which activates PI3K/AKT and MAPK/ERK pathways. Furthermore, CellChat analysis identified robust interactions between EGR4 ⁺ GC cells and cancer-associated fibroblasts (CAFs), particularly extracellular matrix (ECM)-remodeling eCAFs. Secreted GDF15 induced CAF activation through TGF-β receptor signaling, creating a pro-metastatic niche. Collectively, our study establishes the EGR4/GDF15 axis as a critical driver of GC metastasis, offering possible therapeutic targets for intervention.