# CEBPB-Regulated Gastric Cell Plasticity Promotes Liver Metastasis of Gastric Cancer

## TL;DR

This study reveals how gastric cancer cells become more adaptable and spread to the liver, identifying a key protein and potential treatment target.

## Contribution

The study identifies CEBPB as a novel driver of gastric cancer liver metastasis through transcriptional and epigenetic reprogramming.

## Key findings

- Gastric cancer cells reprogram into a high plasticity state during liver metastasis.
- CEBPB activates liver metastasis-associated genes through enhancer reprogramming.
- Blocking CD155–TIGIT interactions inhibits liver metastasis and restores T cell function.

## Abstract

Background: Liver metastasis represents the most common distant dissemination in gastric cancer (GC) but persists as a challenging condition to manage, and its driving molecular mechanisms remain poorly understood. This study aimed to uncover the key regulatory drivers of GC liver metastasis and explore their potential as therapeutic targets. Methods: Herein, we employed a multifaceted approach combining single-cell RNA sequencing, bulk transcriptomics, epigenomics analyses of GC primary tumors and normal adjacent tissues, paired liver metastasis, and circulating tumor cells, alongside in vitro and in vivo experimental validation, to investigate how metastatic GC cells spread to and adapt within the liver microenvironment. Results: We discovered that GC cells undergoing liver metastasis transcriptionally reprogrammed into a high plasticity state. This plasticity was mediated by the transcription factor CCAAT enhancer-binding protein beta (CEBPB), which activated liver metastasis-associated genes through enhancer reprogramming. Notably, CEBPB-driven reprogramming enhanced the metastatic potential of GC cells and enabled them to evade immune surveillance via interactions between cluster of differentiation 155 (CD155) and T cell immunoreceptor with Ig and ITIM domains (TIGIT). Blocking the CD155–TIGIT interplay inhibited liver metastasis and restored T cell cytotoxicity. Conclusions: Our study identifies CEBPB-mediated transcriptional and epigenetic reprogramming as a fundamental driver of GC liver metastasis. Our findings underscore the CEBPB/CD155/TIGIT axis as a promising therapeutic target for liver-metastatic GC.