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LGR5 promotes tumorigenicity and invasion of glioblastoma stem-like cells and is a potential therapeutic target for a subset of glioblastoma patients
Uppsala University, Science for Life Laboratory, SciLifeLab. 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, Science for Life Laboratory, SciLifeLab.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.ORCID iD: 0000-0002-4631-174X
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2019 (English)In: Journal of Pathology, ISSN 0022-3417, E-ISSN 1096-9896, Vol. 247, no 2, p. 228-240Article in journal (Refereed) Published
Abstract [en]

Glioblastoma (GBM) is the most common and lethal primary malignant brain tumor which lacks efficient treatment and predictive biomarkers. Expression of the epithelial stem cell marker Leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5) has been described in GBM, but its functional role has not been conclusively elucidated. Here, we have investigated the role of LGR5 in a large repository of patient-derived GBM stem cell (GSC) cultures. The consequences of LGR5 overexpression or depletion have been analyzed using in vitro and in vivo methods, which showed that, among those with highest LGR5 expression (LGR5(high)), there were two phenotypically distinct groups: one that was dependent on LGR5 for its malignant properties and another that was unaffected by changes in LGR5 expression. The LGR5-responding cultures could be identified by their significantly higher self-renewal capacity as measured by extreme limiting dilution assay (ELDA), and these LGR5(high)-ELDA(high) cultures were also significantly more malignant and invasive compared to the LGR5(high)-ELDA(low) cultures. This showed that LGR5 expression alone would not be a strict marker of LGR5 responsiveness. In a search for additional biomarkers, we identified LPAR4, CCND2, and OLIG2 that were significantly upregulated in LGR5-responsive GSC cultures, and we found that OLIG2 together with LGR5 were predictive of GSC radiation and drug response. Overall, we show that LGR5 regulates the malignant phenotype in a subset of patient-derived GSC cultures, which supports its potential as a predictive GBM biomarker. Copyright (c) 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Place, publisher, year, edition, pages
John Wiley & Sons, 2019. Vol. 247, no 2, p. 228-240
Keywords [en]
glioblastoma stem-like cells, LGR5, self-renewal, invasion, radiation response
National Category
Cancer and Oncology
Identifiers
URN: urn:nbn:se:uu:diva-376723DOI: 10.1002/path.5186ISI: 000456331900009PubMedID: 30357839OAI: oai:DiVA.org:uu-376723DiVA, id: diva2:1287515
Funder
Swedish Research Council, 2012-02591Swedish Cancer Society, 2012/4882015/656Available from: 2019-02-11 Created: 2019-02-11 Last updated: 2019-02-11Bibliographically approved

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Xie, YuanSundström, AndersMaturi, Naga PTan, E-JeanMarinescu, Voichita DJarvius, MalinJin, ChuanChen, LeiEssand, MagnusJohansson, Fredrik J.Nelander, SvenJiang, YiwenUhrbom, Lene

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Xie, YuanSundström, AndersMaturi, Naga PTan, E-JeanMarinescu, Voichita DJarvius, MalinJin, ChuanChen, LeiEssand, MagnusJohansson, Fredrik J.Nelander, SvenJiang, YiwenUhrbom, Lene
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Science for Life Laboratory, SciLifeLabNeuro-OncologyDepartment of Immunology, Genetics and PathologyDepartment of Medical Biochemistry and MicrobiologyCancer Pharmacology and Computational MedicineClinical ImmunologyMolecular tools
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Journal of Pathology
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