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The Human Glioblastoma Cell Culture Resource: Validated Cell Models Representing All Molecular Subtypes
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
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2015 (English)In: EBioMedicine, ISSN 0360-0637, E-ISSN 2352-3964, Vol. 2, no 10, 1351-1363 p.Article in journal (Refereed) Published
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Text
Abstract [en]

Glioblastoma (GBM) is the most frequent and malignant form of primary brain tumor. GBM is essentially incurable and its resistance to therapy is attributed to a subpopulation of cells called gliomastem cells (GSCs). To meet the present shortage of relevant GBM cell (GC) lines we developed a library of annotated and validated cell lines derived from surgical samples of GBM patients, maintained under conditions to preserve GSC characteristics. This collection, which we call the Human Glioblastoma Cell Culture (HGCC) resource, consists of a biobank of 48 GC lines and an associated database containing high-resolution molecular data. We demonstrate that the HGCC lines are tumorigenic, harbor genomic lesions characteristic of GBMs, and represent all four transcriptional sub-types. The HGCC panel provides an open resource for in vitro and in vivo modeling of a large part of GBM diversity useful to both basic and translational GBM research.

Place, publisher, year, edition, pages
2015. Vol. 2, no 10, 1351-1363 p.
Keyword [en]
Glioblastoma, Cell culture, Stem cell culture condition, Molecular subtype, Xenograft models
National Category
Cancer and Oncology Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
URN: urn:nbn:se:uu:diva-274354DOI: 10.1016/j.ebiom.2015.08.026ISI: 000365959700034PubMedID: 26629530OAI: oai:DiVA.org:uu-274354DiVA: diva2:896332
Note

De två sista författarna delar sistaförfattarskapet.

Available from: 2016-01-21 Created: 2016-01-21 Last updated: 2017-11-30Bibliographically approved
In thesis
1. Modeling glioblastoma heterogeneity to decipher its biology
Open this publication in new window or tab >>Modeling glioblastoma heterogeneity to decipher its biology
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Glioblastoma multiforme (GBM) is the most common and lethal form of primary brain tumor that mainly affects adults. GBM displays remarkable intra- and inter-tumoral heterogeneity and contains a subpopulation of cells named glioma stem cells that is believed to be responsible for tumor maintenance, progression and recurrence.

We have established and characterized a biobank of 48 cell lines derived from GBM patients. The cells were explanted and maintained as adherent cultures in serum-free, defined neural stem cell medium. These GBM cells (GCs) displayed NSC marker expression in vitro, had orthotopic tumor initiating capability in vivo, harboured genomic alterations characteristic of GBM and represented all four TCGA molecular subtypes. Our newly established biobank is also connected with a database (www.hgcc.se) that provides all molecular and clinical data. This resource provides a valuable platform of valid in vitro and in vivo models for basic GBM research and drug discovery.

By using RCAS/tv-a mouse models for glioma, we found that GBMs originating from a putative NSC origin caused more tumorigenic GCs that had higher self-renewal abilities than those originating from putative glial precursor cell origin. By transcriptome analysis a mouse cell origin (MCO) gene signature was generated to cluster human GCs and GBM tissue samples and a functional relationship between the differentiation state of the initially transformed cell and the phenotype of GCs was discovered, which provides the basis for a new predictive MCO-based patient classification.

LGR5 was found to be highly expressed in the most malignant mouse GC lines of putative NSC origin and also enriched in proneural GBMs characterized by PDGFRA alterations and OLIG2 up-regulation. By overexpressing or depleting LGR5 we discovered that high LGR5 expression in proneural GC lines increased the tumorigenicity, self-renewal and invasive capacities of the cells and could potentiate WNT signalling through its ligand RSPO1. Through transcriptome analysis we identified the candidate genes CCND2, PDGFRA, OLIG2, DKK1 that were found to be regulated by LGR5.

In the last study, we found that mouse OPCs could initiate both astrocytic and oligdendroglial gliomas, which indicated that oncogenic signalling is dominant to cell of origin in affecting the histology of gliomas.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2016. 49 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206
Keyword
Glioblastoma multiforme, biobank, GBM cells, cell of origin, LGR5, OPCs
National Category
Cancer and Oncology Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-278529 (URN)
Public defence
2016-04-15, Rudbecksalen, Dag Hammarskjold v 20, Uppsala, 09:15 (English)
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Available from: 2016-03-21 Created: 2016-02-24 Last updated: 2016-04-04

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Xie, YuanBergström, TobiasJiang, YiwenJohansson, PatrikMarinescu, Voichita DanaSegerman, AnnaWicher, GrzegorzNiklasson, MiaBaskaran, SathishkumarSreedharan, SmithaKastemar, MarianneHermansson, AnnikaElfineh, LioudmilaLibard, SylwiaHesselager, GöranAlafuzoff, IrinaWestermark, BengtNelander, SvenForsberg-Nilsson, KarinUhrbom, Lene

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Xie, YuanBergström, TobiasJiang, YiwenJohansson, PatrikMarinescu, Voichita DanaSegerman, AnnaWicher, GrzegorzNiklasson, MiaBaskaran, SathishkumarSreedharan, SmithaKastemar, MarianneHermansson, AnnikaElfineh, LioudmilaLibard, SylwiaHesselager, GöranAlafuzoff, IrinaWestermark, BengtNelander, SvenForsberg-Nilsson, KarinUhrbom, Lene
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Neuro-OncologyDepartment of Medical Biochemistry and MicrobiologyDepartment of Immunology, Genetics and PathologyNeurosurgery
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Cancer and OncologyMedical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)

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