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Glioblastoma stem cells express non-canonical proteins and exclusive mesenchymal-like or non-mesenchymal-like protein signatures
Karolinska Inst, Dept Oncol & Pathol, Sci Life Lab, Stockholm, Sweden..
Univ Roma Tor Vergata, Dept Biomed & Prevent, Rome, Italy..
Karolinska Inst, Dept Oncol & Pathol, Sci Life Lab, Stockholm, Sweden..
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer Immunotherapy.ORCID iD: 0000-0002-7088-9533
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2023 (English)In: Molecular Oncology, ISSN 1574-7891, E-ISSN 1878-0261, Vol. 17, no 2, p. 238-260Article in journal (Refereed) Published
Abstract [en]

Glioblastoma (GBM) cancer stem cells (GSCs) contribute to GBM's origin, recurrence, and resistance to treatment. However, the understanding of how mRNA expression patterns of GBM subtypes are reflected at global proteome level in GSCs is limited. To characterize protein expression in GSCs, we performed in-depth proteogenomic analysis of patient-derived GSCs by RNA-sequencing and mass-spectrometry. We quantified > 10 000 proteins in two independent GSC panels and propose a GSC-associated proteomic signature characterizing two distinct phenotypic conditions; one defined by proteins upregulated in proneural and classical GSCs (GPC-like), and another by proteins upregulated in mesenchymal GSCs (GM-like). The GM-like protein set in GBM tissue was associated with necrosis, recurrence, and worse overall survival. Through proteogenomics, we discovered 252 non-canonical peptides in the GSCs, i.e., protein sequences that are variant or derive from genome regions previously considered non-protein-coding, including variants of the heterogeneous ribonucleoproteins implicated in RNA splicing. In summary, GSCs express two protein sets that have an inverse association with clinical outcomes in GBM. The discovery of non-canonical protein sequences questions existing gene models and pinpoints new protein targets for research in GBM.

Place, publisher, year, edition, pages
John Wiley & Sons, 2023. Vol. 17, no 2, p. 238-260
Keywords [en]
glioblastoma stem cells, mesenchymal, proneural, proteogenomics, proteomics, signature
National Category
Cancer and Oncology Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:uu:diva-502261DOI: 10.1002/1878-0261.13355ISI: 000913628600001PubMedID: 36495079OAI: oai:DiVA.org:uu-502261DiVA, id: diva2:1759124
Funder
EU, Horizon 2020, 76428Science for Life Laboratory, SciLifeLabAvailable from: 2023-05-24 Created: 2023-05-24 Last updated: 2023-05-24Bibliographically approved

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Hellström, MatsUhrbom, LeneMaturi, Nagaprathyusha

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