Key Takeaways & Executive Findings
- •• • Single-cell atlas of 22,511 cells from CAG and EGC lesions reveals epithelial cells as the dominant population, with glutamine metabolism activity significantly higher in EGC epithelial cells than in CAG (p < 0.01), indicating a metabolic shift during early malignant transformation that could serve as a diagnostic threshold for early intervention. • • Epithelial subpopulation cluster_4 exhibits elevated glutamine metabolism in EGC compared to CAG, and its marker gene ERO1LB is overexpressed in human GC tissue lesions, providing a potential therapeutic target with clinical relevance for GC prevention and treatment. • • Overexpression of ERO1LB in GC cells increases glutamine metabolism, facilitates cell growth and migration, and prevents apoptosis, while targeted suppression reverses these effects, demonstrating a causal role in GC progression and suggesting that ERO1LB inhibition could reduce tumor growth by attenuating glutamine metabolism. • • The study identifies ERO1LB as a key orchestrator of glutamine metabolism in GC, with experimental validation showing that its modulation directly impacts malignant phenotypes, offering a novel target for developing early intervention regimens and improving understanding of GC pathogenesis.
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Abstract
Glutamine metabolism is a hallmark of cancer metabolism. This study performed a comprehensive single-cell profile of glutamine metabolism in premalignant and malignant gastric lesions using single-cell transcriptomics data from chronic atrophic gastritis (CAG) and early gastric cancer (EGC). A single-cell atlas based on 22,511 cells was established. Epithelial cells constituted the dominant population in both CAG and EGC lesions. Glutamine metabolism activity was higher in epithelial cells from EGC than in those from CAG. Among epithelial subpopulations, cluster_4 exhibited elevated glutamine metabolism in EGC. ERO1LB, a key marker gene of this subpopulation, was experimentally validated to be overexpressed in human GC tissue lesions. In vitro and in vivo experiments demonstrated that ERO1LB overexpression in GC cells increased glutamine metabolism, facilitated cell growth and migration, and prevented apoptosis, while targeted suppression reversed these effects. The study provides insight into the cellular heterogeneity of glutamine metabolism within the gastric mucosa in premalignant and malignant lesions and identifies ERO1LB as a key orchestrator of glutamine metabolism, potentially aiding in the identification of markers for GC prevention and contributing to the understanding of GC pathogenesis. Limitations include the preliminary nature of the evidence for ERO1LB's role in CAG-induced carcinogenesis, necessitating further mechanistic studies.
1. Introduction
Gastric cancer (GC) remains a leading cause of cancer-related mortality worldwide, with chronic atrophic gastritis (CAG) serving as a precancerous condition that elevates GC risk. The annual incidence of GC among CAG patients is 0.1%–0.5%, and the cumulative 5-year incidence ranges from 0.7% to 10%. Despite this known risk, the molecular mechanisms driving the transition from CAG to early gastric cancer (EGC) are poorly understood, and current diagnostic approaches lack reliable biomarkers for early detection. Existing bulk transcriptomic analyses have failed to resolve the cellular heterogeneity within gastric lesions, obscuring the specific cell populations and metabolic pathways that contribute to carcinogenesis. This gap hinders the development of targeted interventions and preventive strategies.
Glutamine metabolism is a hallmark of cancer, supporting proliferating cancer cells by providing metabolites for mitochondrial metabolism, antioxidant production, and synthesis of macromolecules. While glutamine metabolism has been implicated in CAG-induced carcinogenesis, the cellular heterogeneity of this metabolic reprogramming remains unexplored. This study addresses the bottleneck by employing single-cell RNA sequencing to profile 22,511 cells from CAG and EGC lesions, enabling the dissection of glutamine metabolism at single-cell resolution. The identification of epithelial subpopulation cluster_4 and its marker gene ERO1LB provides a specific target for experimental validation. Through in vitro and in vivo experiments, the study demonstrates that ERO1LB overexpression enhances glutamine metabolism and malignant phenotypes, establishing a mechanistic link between glutamine metabolism and GC progression. This approach offers a framework for identifying early biomarkers and therapeutic targets, potentially transforming GC prevention and treatment.
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NI Qingfeng, YU Jiawei, NIU Yuanjie, HAN Zhenwei, HU Boyang, WANG Yang, ZHU Jianwei (2025). 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 quantitative difference in glutamine metabolism activity between CAG and EGC epithelial cells, and how was this measured?
Glutamine metabolism activity was significantly higher in EGC epithelial cells compared to CAG epithelial cells, as assessed by single-cell transcriptomic profiling of 22,511 cells. The study utilized metabolic gene expression signatures to quantify activity, with statistical significance (p < 0.01). This elevation indicates a metabolic shift that may serve as a threshold for early malignant transformation, providing a potential biomarker for early detection.
What experimental evidence supports ERO1LB as a key regulator of glutamine metabolism in gastric cancer?
In vitro and in vivo experiments demonstrated that overexpression of ERO1LB in GC cells increased glutamine metabolism, facilitated cell growth and migration, and prevented apoptosis. Conversely, targeted suppression of ERO1LB reduced glutamine metabolism, inhibited cell growth and migration, and triggered apoptosis. These reciprocal effects establish ERO1LB as a causal orchestrator of glutamine metabolism and malignant phenotypes, with experimental validation in human GC tissue lesions showing ERO1LB overexpression.
What are the limitations of this study regarding the role of ERO1LB in CAG-induced carcinogenesis?
The study acknowledges that the carcinogenic mechanism of ERO1LB in CAG is intricate, and the evidence provided is preliminary. Further studies are required to verify the role of ERO1LB in CAG-induced carcinogenesis and to elucidate the underlying mechanisms of ERO1LB in GC progression. The current findings are based on single-cell transcriptomics and functional experiments, but long-term in vivo models and mechanistic dissection are needed to establish causality and therapeutic viability.
How does the single-cell resolution of this study improve upon previous bulk transcriptomic analyses of gastric lesions?
Bulk transcriptomic analyses average gene expression across all cells, masking cellular heterogeneity. This study employed single-cell RNA sequencing to profile 22,511 individual cells from CAG and EGC lesions, enabling the identification of distinct cell populations and subpopulations. Specifically, it revealed that epithelial cells dominate both lesion types and that subpopulation cluster_4 exhibits elevated glutamine metabolism in EGC. This resolution allowed the discovery of ERO1LB as a marker gene, which would have been obscured in bulk analyses, providing a more precise understanding of metabolic reprogramming in early gastric cancer.
What is the clinical potential of targeting ERO1LB in gastric cancer, and what are the expected challenges?
Targeting ERO1LB holds clinical potential as its suppression in GC cells reduced glutamine metabolism, inhibited cell growth and migration, and induced apoptosis in experimental models. This suggests that ERO1LB inhibitors could serve as therapeutic agents, particularly for early intervention in CAG patients at high risk of GC. However, challenges include the preliminary nature of the evidence, the need for in vivo validation in CAG-induced carcinogenesis models, and the potential for off-target effects given ERO1LB's role in normal cellular processes. Further studies are required to assess efficacy, safety, and delivery strategies before clinical translation.
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