EGR4 transcriptionally upregulates GDF15 to promote gastric cancer metastasis

TL;DR

This study identifies EGR4 and GDF15 as key drivers of gastric cancer metastasis, offering potential new therapeutic targets.

Contribution

The study reveals a novel EGR4/GDF15 signaling axis that promotes gastric cancer metastasis through specific cellular interactions and pathways.

Findings

EGR4 overexpression correlates with reduced survival in gastric cancer patients.

EGR4 activates GDF15 transcription, promoting metastasis via ErbB3/ErbB1 dimerization and downstream signaling pathways.

EGR4+ cancer cells interact with CAFs to create a pro-metastatic environment through GDF15-induced TGF-β signaling.

Abstract

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 bound to the GDF15 promoter, driving its transcriptional activation. Functional studies showed that EGR4 promoted migration and metastasis via GDF15-mediated ErbB3/ErbB1 hetero-dimerization, which activated 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.

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