Single-Cell Transcriptomics Reveals Key Factors in Gastric Intestinal Metaplasia

Gastric cancer is among the deadliest cancers worldwide, and gastric intestinal metaplasia is a key precancerous phase. Understanding the molecular drivers of abnormal proliferation in intestinal metaplasia (IM) is vital for identifying biomarkers and therapeutic targets.

Using single-cell RNA sequencing, we characterized the cellular and molecular dynamics of gastric epithelial tissues across disease stages: control, chronic superficial gastritis, and IM.

We identified nine cell types, predominantly epithelial cells, that exhibited increased proliferation with disease progression, suggesting their role in early gastric carcinogenesis. Notably, the regulatory gene TFF3 was significantly upregulated in IM-associated goblet cells (log₂FC > 1.5, adjusted p-value < 0.001) and correlated strongly with disease advancement. Kyoto Encyclopedia of Genes and Genomes analysis revealed the role of the mitogen-activated protein kinase signaling pathway in early gastric cancer, and copy number variation analysis showed a rise in copy number variations, especially in epithelial cells within the chronic superficial gastritis and IM groups.

These findings suggest that TFF3 may drive the early stages of gastric cancer, although the precise regulatory mechanisms involved remain to be fully elucidated. Additionally, this research may provide valuable insights into the mechanisms underlying other precancerous lesions and related malignancies.