Key Takeaways & Executive Findings
- •• Single-cell transcriptomics reveals higher glutamine metabolism activity in epithelial cells from early gastric cancer (EGC) compared to chronic atrophic gastritis (CAG), with a specific epithelial subpopulation (cluster_4) showing the most pronounced activity. • ERO1LB is identified as a key marker gene of the metabolically active epithelial subpopulation and is overexpressed in human gastric cancer tissues. • Functional experiments demonstrate that ERO1LB overexpression enhances glutamine metabolism, promotes cell growth and migration, and inhibits apoptosis in gastric cancer cells, while knockdown has opposite effects. • The study provides a comprehensive single-cell atlas of glutamine metabolism in premalignant and malignant gastric lesions, offering potential biomarkers for gastric cancer prevention and insights into pathogenesis.
Abstract
Glutamine metabolism is a hallmark of cancer metabolism. This study aims to perform a comprehensive and systematic single-cell profile of glutamine metabolism in premalignant and malignant gastric lesions. We use single-cell transcriptomics data from chronic atrophic gastritis (CAG) and early gastric cancer (EGC) lesions and investigate glutamine metabolism features at the single-cell level. Experiments are implemented to validate the expression and biological role of ERO1LB in gastric cancer (GC). A single-cell atlas based on 22511 cells from premalignant and early-malignant gastric lesions is established. Among these cells, epithelial cells constitute the dominant cell population in both CAG and EGC lesions. The activity of glutamine metabolism is higher in epithelial cells from EGC lesions than in those from CAG lesions. Among the epithelial cell subpopulations, glutamine metabolism is more active in the epithelial cell subpopulation cluster_4 in EGCs than in CAG lesions. As a key marker gene of this subpopulation, ERO1LB is experimentally proven to be overexpressed in human GC tissue lesions. In both in vitro and in vivo experiments, overexpression of ERO1LB in GC cells increases glutamine metabolism, facilitates cell growth and migration and prevents cell apoptosis, and vice versa. This study provides insight into the cellular heterogeneity of glutamine metabolism within the gastric mucosa in premalignant and malignant gastric lesions and identifies ERO1LB as a key orchestrator of glutamine metabolism, which may help to identify markers for GC prevention and contribute to our understanding of GC pathogenesis.
1. Introduction
Chronic atrophic gastritis (CAG) is a gastric precancerous condition with an independent risk of developing into gastric cancer (GC) and constitutes the background for dysplasia and adenocarcinoma together with intestinal metaplasia and dysplasia [1,2]. This disease presents chronic inflammation of the gastric mucosa, accompanied by the loss of gastric glandular cells and replacement by intestinal-type epithelium, pyloric-type glands, or fibrous tissue [3]. Among patients with CAG, the annual incidence (person-year) of GC is 0.1%–0.5% [4], and the cumulative 5-year incidence is 0.7%–10% [5]. Cell type changes play an essential role in the cascade from precancerous to malignant lesions. Nonetheless, the full spectrum of diverse cell types and their molecular features remain to be characterized in gastric premalignant and malignant lesions, hampering investigations of their roles in GC pathogenesis.
Glutamine metabolism is a hallmark of cancer metabolism [6,7]. Proliferating cancer cells depend largely upon glutamine for survival and proliferation [8,9]. Glutamine is the most abundant circulating amino acid in the blood and muscle and is essential for distinct basic cellular functions of tumor cells, e.g., the synthesis of metabolites maintaining mitochondrial metabolism; antioxidant production for eliminating reactive oxygen species; the synthesis of non-essential amino acids, purines, pyrimidines and fatty acid components for cell replication; and the activation of cell signals [10–13]. Glutamine metabolism has been shown to mediate CAG-induced carcinogenesis, but the molecular mechanisms governing this process remain to be explored [14]. Given the pleiotropic roles of glutamine in tumor cells, an in-depth understanding of glutamine metabolism is critical for the discovery of metabolism-based treatments for GC. Identification of the cells responsible for gastric tumorigenesis is important for understanding the molecular underpinnings of tumor evolution. Single-cell transcriptomics is a powerful tool for deciphering the cellular and molecular landscape at single-cell resolution, unlike bulk transcriptomics, which provides averaged data [15]. The application of single-cell transcriptomics has revolutionized our understanding of the biological features and dynamics within tumor lesions [16–18]. Hence, this study presents a single-cell map of glutamine metabolism in the gastric mucosa of patients with premalignant and malignant gastric lesions and reveals that ERO1LB is a key orchestrator that modulates glutamine metabolism.
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Qingfeng Ni, Jiawei Yu, Yuanjie Niu, Zhenwei Han, Boyang Hu, Yang Wang, Jianwei Zhu (2026). Single-cell transcriptomic data reveal the cellular heterogeneity of glutamine metabolism in gastric premalignant lesions and early gastric cancer. Acta Biochimica et Biophysica Sinica. https://doi.org/10.3724/abbs.2025061
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Frequently Asked Questions
What is the main finding of this study?
The study reveals cellular heterogeneity in glutamine metabolism within gastric premalignant and early cancerous lesions, identifying ERO1LB as a key orchestrator that promotes glutamine metabolism, cell growth, and migration while inhibiting apoptosis in gastric cancer cells.
How was the single-cell analysis performed?
Single-cell transcriptomic data from chronic atrophic gastritis (CAG) and early gastric cancer (EGC) samples were obtained from the GSE134520 dataset and analyzed to profile glutamine metabolism at single-cell resolution.
What is the role of ERO1LB in gastric cancer?
ERO1LB is overexpressed in gastric cancer tissues and functionally enhances glutamine metabolism, promotes cell proliferation and migration, and suppresses apoptosis, as demonstrated by in vitro and in vivo experiments.
What are the clinical implications of this research?
The findings may help identify biomarkers for gastric cancer prevention and provide insights into the pathogenesis of gastric cancer, potentially leading to metabolism-based therapeutic strategies.
Which cell populations show the highest glutamine metabolism activity?
Epithelial cells, particularly a subpopulation designated cluster_4, exhibit higher glutamine metabolism activity in early gastric cancer lesions compared to chronic atrophic gastritis lesions.
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