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Primary glioblastoma cells for precision medicine: a quantitative portrait of genomic (in)stability during the first 30 passages
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 Medical Sciences, Cancer Pharmacology and Computational Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.ORCID iD: 0000-0003-3403-0083
Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
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2018 (English)In: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 20, no 8, p. 1080-1091Article in journal (Refereed) Published
Abstract [en]

Background: Primary glioblastoma cell (GC) cultures have emerged as a key model in brain tumor research, with the potential to uncover patient-specific differences in therapy response. However, there is limited quantitative information about the stability of such cells during the initial 20-30 passages of culture.

Methods: We interrogated 3 patient-derived GC cultures at dense time intervals during the first 30 passages of culture. Combining state-of-the-art signal processing methods with a mathematical model of growth, we estimated clonal composition, rates of change, affected pathways, and correlations between altered gene dosage and transcription.

Results: We demonstrate that GC cultures undergo sequential clonal takeovers, observed through variable proportions of specific subchromosomal lesions, variations in aneuploid cell content, and variations in subpopulation cell cycling times. The GC cultures also show significant transcriptional drift in several metabolic and signaling pathways, including ribosomal synthesis, telomere packaging and signaling via the mammalian target of rapamycin, Wnt, and interferon pathways, to a high degree explained by changes in gene dosage. In addition to these adaptations, the cultured GCs showed signs of shifting transcriptional subtype. Compared with chromosomal aberrations and gene expression, DNA methylations remained comparatively stable during passaging, and may be favorable as a biomarker.

Conclusion: Taken together, GC cultures undergo significant genomic and transcriptional changes that need to be considered in functional experiments and biomarker studies that involve primary glioblastoma cells.

Place, publisher, year, edition, pages
OXFORD UNIV PRESS INC , 2018. Vol. 20, no 8, p. 1080-1091
Keywords [en]
aneuploidy, clones, GBM DNA methylation, GBM subtype, glioma stem cell cultures, patient derived GBM cell cultures, systems biology
National Category
Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:uu:diva-361042DOI: 10.1093/neuonc/noy024ISI: 000438338000009PubMedID: 29462414OAI: oai:DiVA.org:uu-361042DiVA, id: diva2:1249818
Funder
Swedish Research Council, 2014-03314Swedish Cancer Society, CAN 2017/628Swedish Foundation for Strategic Research , BD15-088Available from: 2018-09-20 Created: 2018-09-20 Last updated: 2018-09-20Bibliographically approved

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Baskaran, SathishkumarMayrhofer, MarkusGöransson Kultima, HannaBergström, TobiasElfineh, LioudmilaCavelier, LuciaIsaksson, AndersNelander, Sven

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Baskaran, SathishkumarMayrhofer, MarkusGöransson Kultima, HannaBergström, TobiasElfineh, LioudmilaCavelier, LuciaIsaksson, AndersNelander, Sven
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Neuro-OncologyCancer Pharmacology and Computational MedicineScience for Life Laboratory, SciLifeLabDepartment of Medical SciencesMedicinsk genetik och genomik
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