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Glioma classification based on mass spectrometry imaging to spatially resolved proteomic and clinical data open a new stratification of patients for a more adaptated treatment

ABSTRACT: Gliomas represent 80% of all malignant cerebral tumors and are classified within different malignity grade. Glioblastoma, the most aggressive group, represent more than half of all gliomas but remain a heterogeneous group. Indeed, patient survival can reach from several months to a few years after surgery and chemotherapy. To study gliomas, MALDI mass spectrometry imaging is an interesting technique, allowing the analysis of tumor heterogeneity. In this study, MALDI-MSI is coupled with spatially-resolved microproteomic within the objective to identify subgroups of glioblastomas patients in order to help diagnosis and prognostic. Molecular images are generated from thin tissue section in order to determine the spatial localization of digested peptides. Thanks to unsupervised statistical analysis, we then generated hierarchical clustering of homogeneous molecular regions. According to these regions, spatially resolved proteomic gave access to large scale protein identification and relative quantification. Hierarchical clustering reveal three molecular region within all the tumors sample : region red which represent 33% of surface of all sample, region yellow (25.7%) and region blue (40.8%). Consequently, 3 groups of patient can be determined: group A composed mostly of region red (13/50 patients), group B composed mostly of region yellow (9/50 patients) and group C composed mostly of region blue (24/50 patients). Spatially resolved proteomic was performed and the 147 extractions were analyzed by nano-LC MS/MS. Two-way ANOVA test reveal panel of proteins specifically overexpressed in each region. Protein overexpressed in region red are associated with neurogenesis; protein overexpressed in region yellow are associated with an activation of the immune system and protein overexpressed in region blue are involved with viral processes. To conclude, the combination of MALDI-MSI and microproteomic provides new information on these tumors, allowing us to differentiate three group of patient. In the future, these data will permit to build a more precise classification, a better medical care for patients and the identification of potential new therapeutic targets.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Brain

DISEASE(S): Brain Glioblastoma Multiforme

SUBMITTER: Lauranne Drelich

LAB HEAD: Michel Salzet

PROVIDER: PXD016165 | Pride | 2023-03-10

REPOSITORIES: Pride

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Publications

Spatial analysis of the glioblastoma proteome reveals specific molecular signatures and markers of survival.

Duhamel Marie M Drelich Lauranne L Wisztorski Maxence M Aboulouard Soulaimane S Gimeno Jean-Pascal JP Ogrinc Nina N Devos Patrick P Cardon Tristan T Weller Michael M Escande Fabienne F Zairi Fahed F Maurage Claude-Alain CA Le Rhun Émilie É Fournier Isabelle I Salzet Michel M

Nature communications 20221104 1

Molecular heterogeneity is a key feature of glioblastoma that impedes patient stratification and leads to large discrepancies in mean patient survival. Here, we analyze a cohort of 96 glioblastoma patients with survival ranging from a few months to over 4 years. 46 tumors are analyzed by mass spectrometry-based spatially-resolved proteomics guided by mass spectrometry imaging. Integration of protein expression and clinical information highlights three molecular groups associated with immune, neu ...[more]

PMID: 36333286

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Project description:The different clinical behavior of low and high grade gliomas and the chance to develop novel selective agents that specifically target tumor-associated proteins in gliomas stimulate the research of molecules playing a role in glioma progression. Gene expression profiling using microarrays allows the study at the same time of the expression patterns of thousands of genes in tumor cells. In the present study microarrays with about 20,000 genes have been employed to discover the gene expression profile in 39 glial neoplasias (28 glioblastomas (GBM) and 11 low grade gliomas, namely 4 oligodendrogliomas, 5 pilocytic astrocytomas (PA), 2 fibrillary astrocytomas (FA)). Unsupervised classification through hierarchical cluster analysis identified 2 groups of tumours: one group mainly composed of low grade malignant tumours (10 low grade gliomas and 3 GBM), the other one constituted by GBM, with the exception of one low grade case. The nearest shrunken centroid classification method was used to identify genes useful to classify and best characterize high and low grade gliomas. [Tibshirani et al. 2002]; This procedure selected 9 genes as most informative for the classification task: ; Among them 7 genes were overexpressed in low grade gliomas, but underexpressed in GBM; on the contrary 2 genes were overexpressed in GBM, but underexpressed in low grade tumours; Forty five tumors were immunostained for IGFBP-2 . 81,5% GBM resulted immunopositive. On the contrary only one low grade glioma was positive. Gene expression profiling and immunohistochemistry suggest that IGFBP-2 may play a role in glioma progression. IGFBP-2 appears to be a novel immunohistochemical marker of malignancy in glial tumours and probably is the basis for targeted chemotherapy. Experiment Overall Design: We retrieved for this study 185 randomly selected cases of gliomas. All the cases had been received unfixed. A sample of neoplastic tissue had been flash frozen over liquid nitrogen and stored at -80Â°C into the frozen tissue bank of the Section of Pathology of Bellaria Hospital between 1990 and 2002. The remaining (specular) tissues were formalin fixed and paraffin embedded for routine histologic diagnosis. Experiment Overall Design: In the present investigation, only samples with rRNA 28S/18S ratio > 1.0 measured by Bioanalyzer 2100 (Agilent)and no evidence of ribosomal degradation were included. Some cases were excluded as the tissue samples were composed only by necrosis; other cases did not show neoplastic proliferation. Therefore only 39 glial neoplasias were suitable for the study: i.e. 28 GBMs and 11 low grade CNS tumors, namely 4 oligodendrogliomas (OL), 5 pilocytic astrocytomas (PA), 2 fibrillary astrocytoma (FA) showed a good quality of RNA. Experiment Overall Design: All the tumors were re-staged and graded according to 2000 WHO criteria at time of gene expression analysis by two pathologists (GM and VE). Experiment Overall Design: 39 glial neoplasias were labeled by Cy5. Common reference pool consisted of a mixture of total RNA from the low grade CNS tumor group (4 OL, 5 PA, 2 FA) labeled by Cy3. A series of the most informative genes were confirmed by RT-qPCR. Experiment Overall Design:

			Action	DRS
	MS-MS-file.zip	Other
	experimentalDesignTemplate.txt	Txt
	modificationSpecificPeptides.txt	Txt
	parameters.txt	Txt
	peptides.txt	Txt