Proteomic profiling of gliomas unveils immune and metabolism-driven subtypes with implications for anti-nucleotide metabolism therapy

Jinsen Zhang, Rui Sun, Yingying Lyu, Chaxian Liu, Ying Liu, Yuan Feng, Minjie Fu, Peter Jih Cheng Wong, Zunguo Du, Tianming Qiu, Yi Zhang, Dongxiao Zhuang, Zhiyong Qin, Yu Yao, Wei Zhu, Tiannan Guo, Wei Hua (), Hui Yang () and Ying Mao ()
Additional contact information
Jinsen Zhang: Fudan University
Rui Sun: Westlake University
Yingying Lyu: Fudan University
Chaxian Liu: Fudan University
Ying Liu: Fudan University
Yuan Feng: Fudan University
Minjie Fu: Fudan University
Peter Jih Cheng Wong: Fudan University
Zunguo Du: Fudan University
Tianming Qiu: Fudan University
Yi Zhang: Fudan University
Dongxiao Zhuang: Fudan University
Zhiyong Qin: Fudan University
Yu Yao: Fudan University
Wei Zhu: Fudan University
Tiannan Guo: Westlake University
Wei Hua: Fudan University
Hui Yang: Fudan University
Ying Mao: Fudan University

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: Abstract Gliomas exhibit high heterogeneity and poor prognosis. Despite substantial progress has been made at the genomic and transcriptomic levels, comprehensive proteomic characterization and its implications remain largely unexplored. In this study, we perform proteomic profiling of gliomas using 343 formalin-fixed and paraffin-embedded tumor samples and 53 normal-appearing brain samples from 188 patients, integrating these data with genomic panel information and clinical outcomes. The proteomic analysis uncovers two distinct subgroups: Subgroup 1, the metabolic neural subgroup, enriched in metabolic enzymes and neurotransmitter receptor proteins, and Subgroup 2, the immune subgroup, marked by upregulation of immune and inflammatory proteins. These proteomic subgroups show significant differences in prognosis, tumorigenesis, microenvironment dysregulation, and potential therapeutics, highlighting the critical roles of metabolic and immune processes in glioma biology and patient outcomes. Through a detailed investigation of metabolic pathways guided by our proteomic findings, dihydropyrimidine dehydrogenase (DPYD) and thymidine phosphorylase (TYMP) emerge as potential prognostic biomarkers linked to the reprogramming of nucleotide metabolism. Functional validation in patient-derived glioma stem cells and animal models highlights nucleotide metabolism as a promising therapy target for gliomas. This integrated multi-omics analysis introduces a proteomic classification for gliomas and identifies DPYD and TYMP as key metabolic biomarkers, offering insights into glioma pathogenesis and potential treatment strategies.

Date: 2024
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DOI: 10.1038/s41467-024-54352-5

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