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Modeling glioblastoma heterogeneity to decipher its biology
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
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 [en]
Glioblastoma multiforme, biobank, GBM cells, cell of origin, LGR5, OPCs
National Category
Cancer and Oncology Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:uu:diva-278529OAI: oai:DiVA.org:uu-278529DiVA: diva2:906880
Public defence
2016-04-15, Rudbecksalen, Dag Hammarskjold v 20, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2016-03-21 Created: 2016-02-24 Last updated: 2016-04-04
List of papers
1. The Human Glioblastoma Cell Culture Resource: Validated Cell Models Representing All Molecular Subtypes
Open this publication in new window or tab >>The Human Glioblastoma Cell Culture Resource: Validated Cell Models Representing All Molecular Subtypes
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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
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.

Keyword
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:nbn:se:uu:diva-274354 (URN)10.1016/j.ebiom.2015.08.026 (DOI)000365959700034 ()26629530 (PubMedID)
Note

De två sista författarna delar sistaförfattarskapet.

Available from: 2016-01-21 Created: 2016-01-21 Last updated: 2017-11-30Bibliographically approved
2. Malignancy and drug sensitivity of glioblastoma cells are affected by the cell of origin
Open this publication in new window or tab >>Malignancy and drug sensitivity of glioblastoma cells are affected by the cell of origin
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(English)Manuscript (preprint) (Other academic)
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-278446 (URN)
Available from: 2016-02-24 Created: 2016-02-24 Last updated: 2016-04-04
3. High LGR5 expression in proneural glioblastoma cells contributes to increased self-renewal and invasiveness
Open this publication in new window or tab >>High LGR5 expression in proneural glioblastoma cells contributes to increased self-renewal and invasiveness
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(English)Manuscript (preprint) (Other academic)
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-278514 (URN)
Available from: 2016-02-24 Created: 2016-02-24 Last updated: 2016-04-04
4. Oncogenic Signaling Is Dominant to Cell of Origin and Dictates Astrocytic or Oligodendroglial Tumor Development from Oligodendrocyte Precursor Cells
Open this publication in new window or tab >>Oncogenic Signaling Is Dominant to Cell of Origin and Dictates Astrocytic or Oligodendroglial Tumor Development from Oligodendrocyte Precursor Cells
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2014 (English)In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 34, no 44, 14644-14651 p.Article in journal (Refereed) Published
Abstract [en]

Stem cells, believed to be the cellular origin of glioma, are able to generate gliomas, according to experimental studies. Here we investigated the potential and circumstances of more differentiated cells to generate glioma development. We and others have shown that oligodendrocyte precursor cells (OPCs) can also be the cell of origin for experimental oligodendroglial tumors. However, the question of whether OPCs have the capacity to initiate astrocytic gliomas remains unanswered. Astrocytic and oligodendroglial tumors represent the two most common groups of glioma and have been considered as distinct disease groups with putatively different origins. Here we show that mouse OPCs can give rise to both types of glioma given the right circumstances. We analyzed tumors induced by K-RAS and AKT and compared them to oligodendroglial platelet-derived growth factor B-induced tumors in Ctv-a mice with targeted deletions of Cdkn2a (p16(Ink4a-/-), p19(Arf-/-), Cdkn2a(-/-)). Our results showed that glioma can originate from OPCs through overexpression of K-RAS and AKT when combined with p19(Arf) loss, and these tumors displayed an astrocytic histology and high expression of astrocytic markers. We argue that OPC shave the potential to develop both astrocytic and oligodendroglial tumors given loss of p19(Arf), and that oncogenic signaling is dominant to cell of origin in determining glioma phenotype. Our mouse data are supported by the fact that human astrocytoma and oligodendroglioma display a high degree of overlap in global gene expression with no clear distinctions between the two diagnoses.

Keyword
astrocytoma, cell of origin, glioma, low-grade glioma, oligodendroglioma, PDGF
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-240010 (URN)10.1523/JNEUROSCI.2977-14.2014 (DOI)000345220100014 ()25355217 (PubMedID)
Available from: 2015-01-05 Created: 2015-01-05 Last updated: 2017-12-05Bibliographically approved

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