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.

Comprehensive molecular characterisations could shed light on the high heterogeneity and poor prognosis of gliomas. Here, the authors perform proteomic profiling of 188 glioma patients, revealing immune and metabolic neuron-related subgroups as well as metabolic biomarkers linked to prognosis.

Details

Title
Proteomic profiling of gliomas unveils immune and metabolism-driven subtypes with implications for anti-nucleotide metabolism therapy
Author
Zhang, Jinsen 1 ; Sun, Rui 2 ; Lyu, Yingying 1 ; Liu, Chaxian 1 ; Liu, Ying 3 ; Feng, Yuan 1 ; Fu, Minjie 1 ; Wong, Peter Jih Cheng 1   VIAFID ORCID Logo  ; Du, Zunguo 4 ; Qiu, Tianming 1 ; Zhang, Yi 1 ; Zhuang, Dongxiao 1 ; Qin, Zhiyong 1 ; Yao, Yu 1 ; Zhu, Wei 1   VIAFID ORCID Logo  ; Guo, Tiannan 2 ; Hua, Wei 1   VIAFID ORCID Logo  ; Yang, Hui 5   VIAFID ORCID Logo  ; Mao, Ying 1   VIAFID ORCID Logo 

1  Fudan University, Department of Neurosurgery, Huashan Hospital, Shanghai, China (GRID:grid.8547.e) (ISNI:0000 0001 0125 2443); National Center for Neurological Disorders, Shanghai, China (GRID:grid.8547.e); Shanghai Key Laboratory of Brain Function Restoration and Neural Regeneration, Shanghai, China (GRID:grid.22069.3f) (ISNI:0000 0004 0369 6365); Neurosurgical Institute of Fudan University, Shanghai, China (GRID:grid.8547.e) (ISNI:0000 0001 0125 2443); Shanghai Clinical Medical Center of Neurosurgery, Shanghai, China (GRID:grid.411405.5) (ISNI:0000 0004 1757 8861) 
2  Westlake University, Affiliated Hangzhou First People’s Hospital, State Key Laboratory of Medical Proteomics, School of Medicine, Hangzhou, China (GRID:grid.494629.4) (ISNI:0000 0004 8008 9315); Westlake Laboratory of Life Sciences and Biomedicine, Westlake Center for Intelligent Proteomics, Hangzhou, China (GRID:grid.494629.4) (ISNI:0000 0004 8008 9315); Westlake University, Research Center for Industries of the Future, School of Life Sciences, Hangzhou, China (GRID:grid.494629.4) (ISNI:0000 0004 8008 9315) 
3  Fudan University, Department of Pathology, Shanghai Medical College, Shanghai, China (GRID:grid.8547.e) (ISNI:0000 0001 0125 2443) 
4  Fudan University, Department of Pathology, Huashan Hospital, Shanghai, China (GRID:grid.8547.e) (ISNI:0000 0001 0125 2443) 
5  Fudan University, Department of Neurosurgery, Huashan Hospital, Shanghai, China (GRID:grid.8547.e) (ISNI:0000 0001 0125 2443); National Center for Neurological Disorders, Shanghai, China (GRID:grid.8547.e); Shanghai Key Laboratory of Brain Function Restoration and Neural Regeneration, Shanghai, China (GRID:grid.22069.3f) (ISNI:0000 0004 0369 6365); Neurosurgical Institute of Fudan University, Shanghai, China (GRID:grid.8547.e) (ISNI:0000 0001 0125 2443); Shanghai Clinical Medical Center of Neurosurgery, Shanghai, China (GRID:grid.411405.5) (ISNI:0000 0004 1757 8861); Fudan University, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institute for Translational Brain Research, Shanghai Medical College, Shanghai, China (GRID:grid.8547.e) (ISNI:0000 0001 0125 2443) 
Pages
10005
Publication year
2024
Publication date
2024
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-024-54352-5
ProQuest document ID
3130567976
Copyright
© The Author(s) 2024. This work is published under http://creativecommons.org/licenses/by-nc-nd/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.