Integrating multiple machine learning methods to construct glutamine metabolism-related signatures in lung adenocarcinoma

Pengpeng Zhang; Shengbin Pei; Leilei Wu; Zhijia Xia; Qi Wang; Xufeng Huang; Zhangzuo Li; Jiaheng Xie; Mingjun Du; Haoran Lin

doi:10.3389/fendo.2023.1196372

Integrating multiple machine learning methods to construct glutamine metabolism-related signatures in lung adenocarcinoma

Front Endocrinol (Lausanne). 2023 May 17:14:1196372. doi: 10.3389/fendo.2023.1196372. eCollection 2023.

Authors

Pengpeng Zhang¹, Shengbin Pei², Leilei Wu³, Zhijia Xia⁴, Qi Wang⁵, Xufeng Huang⁶, Zhangzuo Li⁷, Jiaheng Xie⁸, Mingjun Du¹, Haoran Lin¹

Affiliations

¹ Department of Thoracic Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
² Department of Breast Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
³ Department of Radiation Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China.
⁴ Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, Munich, Germany.
⁵ Department of Gastroenterology, Affiliated Hospital of Jiangsu University, Jiangsu University, Zhenjiang, China.
⁶ Faculty of Dentistry, University of Debrecen, Debrecen, Hungary.
⁷ Department of Cell Biology, School of Medicine, Jiangsu University, Zhenjiang, China.
⁸ Department of Burns and Plastic Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.

Abstract

Background: Glutamine metabolism (GM) is known to play a critical role in cancer development, including in lung adenocarcinoma (LUAD), although the exact contribution of GM to LUAD remains incompletely understood. In this study, we aimed to discover new targets for the treatment of LUAD patients by using machine learning algorithms to establish prognostic models based on GM-related genes (GMRGs).

Methods: We used the AUCell and WGCNA algorithms, along with single-cell and bulk RNA-seq data, to identify the most prominent GMRGs associated with LUAD. Multiple machine learning algorithms were employed to develop risk models with optimal predictive performance. We validated our models using multiple external datasets and investigated disparities in the tumor microenvironment (TME), mutation landscape, enriched pathways, and response to immunotherapy across various risk groups. Additionally, we conducted in vitro and in vivo experiments to confirm the role of LGALS3 in LUAD.

Results: We identified 173 GMRGs strongly associated with GM activity and selected the Random Survival Forest (RSF) and Supervised Principal Components (SuperPC) methods to develop a prognostic model. Our model's performance was validated using multiple external datasets. Our analysis revealed that the low-risk group had higher immune cell infiltration and increased expression of immune checkpoints, indicating that this group may be more receptive to immunotherapy. Moreover, our experimental results confirmed that LGALS3 promoted the proliferation, invasion, and migration of LUAD cells.

Conclusion: Our study established a prognostic model based on GMRGs that can predict the effectiveness of immunotherapy and provide novel approaches for the treatment of LUAD. Our findings also suggest that LGALS3 may be a potential therapeutic target for LUAD.

Keywords: glutamine; lung adenocarcinoma; machine learning; prognosis; signature.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenocarcinoma of Lung* / genetics
Galectin 3
Glutamine
Humans
Lung Neoplasms* / genetics
Machine Learning
Tumor Microenvironment / genetics

Substances

Glutamine
Galectin 3

Grants and funding

This study was supported by Natural Science Foundation of Jiangsu Province (BK20210956) and the High-level Innovation and Entrepreneurship Talent Introduction Plan of Jiangsu Province (JSSCBS20211459).