# 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.

## Key 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.