Dissecting gastric cancer heterogeneity and exploring therapeutic strategies using bulk and single-cell transcriptomic analysis and experimental validation of tumor microenvironment and metabolic interplay

XianTao Lin; Ping Yang; MingKun Wang; Xiuting Huang; Baiyao Wang; Chengcong Chen; Anan Xu; Jiazuo Cai; Muhammad Khan; Sha Liu; Jie Lin

doi:10.3389/fphar.2024.1355269

Dissecting gastric cancer heterogeneity and exploring therapeutic strategies using bulk and single-cell transcriptomic analysis and experimental validation of tumor microenvironment and metabolic interplay

Front Pharmacol. 2024 Jun 19:15:1355269. doi: 10.3389/fphar.2024.1355269. eCollection 2024.

Authors

XianTao Lin^#¹, Ping Yang^#¹, MingKun Wang^#¹, Xiuting Huang², Baiyao Wang², Chengcong Chen², Anan Xu², Jiazuo Cai², Muhammad Khan², Sha Liu¹, Jie Lin²

Affiliations

¹ Department of Radiation Oncology, Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China.
² Department of Radiotherapy, The First Affiliated Hospital of Hainan Medical University, Haikou, China.

^# Contributed equally.

Abstract

Gastric cancer, the fifth most prevalent cancer worldwide, is often diagnosed in advanced stages with limited treatment options. Examining the tumor microenvironment (TME) and its metabolic reprogramming can provide insights for better diagnosis and treatment. This study investigates the link between TME factors and metabolic activity in gastric cancer using bulk and single-cell RNA-sequencing data. We identified two molecular subtypes in gastric cancer by analyzing the distinct expression patterns of 81 prognostic genes related to the TME and metabolism, which exhibited significant protein-level interactions. The high-risk subtype had increased stromal content, fibroblast and M2 macrophage infiltration, elevated glycosaminoglycans/glycosphingolipids biosynthesis, and fat metabolism, along with advanced clinicopathological features. It also exhibited low mutation rates and microsatellite instability, associating it with the mesenchymal phenotype. In contrast, the low-risk group showed higher tumor content and upregulated protein and sugar metabolism. We identified a 15-gene prognostic signature representing these characteristics, including CPVL, KYNU, CD36, and GPX3, strongly correlated with M2 macrophages, validated through single-cell analysis and an internal cohort. Despite resistance to immunotherapy, the high-risk group showed sensitivity to molecular targeted agents directed at IGF-1R (BMS-754807) and the PI3K-mTOR pathways (AZD8186, AZD8055). We experimentally validated these promising drugs for their inhibitory effects on MKN45 and MKN28 gastric cells. This study unveils the intricate interplay between TME and metabolic pathways in gastric cancer, offering potential for enhanced diagnosis, patient stratification, and personalized treatment. Understanding molecular features in each subtype enriches our comprehension of gastric cancer heterogeneity and potential therapeutic targets.

Keywords: M2 macrophage; cancer metabolism; gastric cancer; single-cell analysis; tumor microenvironment.

Grants and funding

The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. This work was supported by the National Natural Science Foundation of China (No. 82102974), Science and Technology Program of Guangzhou, China (202201011048), Guangzhou Key Medical Discipline Construction Project Fund, Key Clinical Technology of Guangzhou (2019ZD17). Hainan Province Clinical Medical Centre. Beijing Science And Technology Innovation Medical Development Foundation (KC2023-JX-0186-BQ081).