title: Micro-environment causes reversible changes in DNA methylation and mRNA expression profiles in patient-derived glioma stem cells.
abstract: In vitro and in vivo models are widely used in cancer research. Characterizing the similarities and differences between a patient's tumor and corresponding in vitro and in vivo models is important for understanding the potential clinical relevance of experimental data generated with these models. Towards this aim, we analyzed the genomic aberrations, DNA methylation and transcriptome profiles of five parental tumors and their matched in vitro isolated glioma stem cell (GSC) lines and xenografts generated from these same GSCs using high-resolution platforms. We observed that the methylation and transcriptome profiles of in vitro GSCs were significantly different from their corresponding xenografts, which were actually more similar to their original parental tumors. This points to the potentially critical role of the brain microenvironment in influencing methylation and transcriptional patterns of GSCs. Consistent with this possibility, ex vivo cultured GSCs isolated from xenografts showed a tendency to return to their initial in vitro states even after a short time in culture, supporting a rapid dynamic adaptation to the in vitro microenvironment. These results show that methylation and transcriptome profiles are highly dependent on the microenvironment and growth in orthotopic sites partially reverse the changes caused by in vitro culturing.
authors.affiliation: New York University Cancer Institute, New York University Brain Tumor Center, New York University Langone Medical Center, New York, New York, United States of America.
authors.forename: Mehmet
authors.initials: M
authors.lastname: Baysan
authors.affiliation: Department of Pathology, Microbiology, and Immunology, University of California Davis, Davis, California, United States of America.
authors.forename: Kevin
authors.initials: K
authors.lastname: Woolard
authors.affiliation: Department of Mathematics, Statistics, and Computer Science, Marquette University, Milwaukee, Wisconsin, United States of America.
authors.forename: Serdar
authors.initials: S
authors.lastname: Bozdag
authors.affiliation: Neuro-Oncology Branch, National Cancer Institute, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Gregory
authors.initials: G
authors.lastname: Riddick
authors.affiliation: Neuro-Oncology Branch, National Cancer Institute, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Svetlana
authors.initials: S
authors.lastname: Kotliarova
authors.affiliation: Neuro-Oncology Branch, National Cancer Institute, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Margaret C
authors.initials: MC
authors.lastname: Cam
authors.affiliation: Neuro-Oncology Branch, National Cancer Institute, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Galina I
authors.initials: GI
authors.lastname: Belova
authors.affiliation: Neuro-Oncology Branch, National Cancer Institute, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Susie
authors.initials: S
authors.lastname: Ahn
authors.affiliation: Neuro-Oncology Branch, National Cancer Institute, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Neuro-Oncology Branch, National Cancer Institute, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Hua
authors.initials: H
authors.lastname: Song
authors.affiliation: Genetics Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Walling
authors.affiliation: Genetics Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Holly
authors.initials: H
authors.lastname: Stevenson
authors.affiliation: Genetics Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Paul
authors.initials: P
authors.lastname: Meltzer
authors.affiliation: New York University Cancer Institute, New York University Brain Tumor Center, New York University Langone Medical Center, New York, New York, United States of America.
authors.forename: Howard A
authors.initials: HA
authors.lastname: Fine
mesh_terms: D000818:Animals; D019175:DNA Methylation / Q000235:genetics / Q000502:physiology; D005260:Female; D005910:Glioma / Q000235:genetics*; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D016513:Mice, SCID; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D025341:Principal Component Analysis; D011446:Prospective Studies; D014407:Tumor Cells, Cultured
references.citation: Integr Biol (Camb). 2011 Apr;3(4):439-50
references.pmid: 21135965
references.citation: Cell Stem Cell. 2012 May 4;10(5):620-34
references.pmid: 22560082
references.citation: Cell Biochem Funct. 2010 Jul;28(5):343-51
references.pmid: 20535838
references.citation: Nat Genet. 2013 Oct;45(10):1141-9
references.pmid: 23917401
references.citation: Nature. 2008 Aug 7;454(7205):766-70
references.pmid: 18600261
references.citation: Neurosurg Focus. 2014 Apr;36(4):E23
references.pmid: 24812719
references.citation: Nat Genet. 2000 May;25(1):25-9
references.pmid: 10802651
references.citation: Nature. 2010 Dec 9;468(7325):824-8
references.pmid: 21102434
references.citation: Genomics. 2011 Oct;98(4):288-95
references.pmid: 21839163
references.citation: Cell. 2011 Oct 14;147(2):370-81
references.pmid: 22000015
references.citation: Epigenomics. 2011 Dec;3(6):771-84
references.pmid: 22126295
references.citation: Proc Natl Acad Sci U S A. 2011 Mar 15;108(11):4274-80
references.pmid: 21262804
references.citation: PLoS One. 2012;7(12):e51407
references.pmid: 23236496
references.citation: Cancer Res. 2012 Nov 15;72(22):6065-75
references.pmid: 22986743
references.citation: Proc Natl Acad Sci U S A. 2007 Dec 11;104(50):20007-12
references.pmid: 18077431
references.citation: Cancer Res. 2009 Mar 1;69(5):2091-9
references.pmid: 19244127
references.citation: Science. 2012 Sep 7;337(6099):1231-5
references.pmid: 22837387
references.citation: Nature. 2012 Aug 23;488(7412):522-6
references.pmid: 22854781
references.citation: PLoS One. 2012;7(11):e47839
references.pmid: 23139755
references.citation: Nat Struct Mol Biol. 2009 Mar;16(3):304-311
references.pmid: 19234465
references.citation: Genes Dev. 2010 Aug 15;24(16):1731-45
references.pmid: 20713517
references.citation: Cancer Cell. 2006 May;9(5):391-403
references.pmid: 16697959
references.citation: Cell. 2012 Mar 30;149(1):36-47
references.pmid: 22464322
references.citation: Cancer Cell. 2010 Jan 19;17(1):98-110
references.pmid: 20129251
references.citation: Cancer Cell. 2010 May 18;17(5):510-22
references.pmid: 20399149
references.citation: Expert Opin Drug Discov. 2011 Dec;6(12):1271-83
references.pmid: 22647066
references.citation: Proc Natl Acad Sci U S A. 2012 Feb 21;109(8):3041-6
references.pmid: 22323597
references.citation: J Neuropathol Exp Neurol. 2002 Mar;61(3):215-25; discussion 226-9
references.pmid: 11895036
references.citation: Biochem Pharmacol. 2013 Mar 1;85(5):612-622
references.pmid: 23063412
references.citation: Cancer Cell. 2013 Sep 9;24(3):331-46
references.pmid: 23993863
references.citation: PLoS One. 2013 Apr 29;8(4):e62982
references.pmid: 23658659
references.citation: Cell. 2013 Oct 10;155(2):462-77
references.pmid: 24120142
references.citation: Nature. 2012 Feb 15;483(7390):479-83
references.pmid: 22343889
references.citation: Aging Cell. 2010 Feb;9(1):54-63
references.pmid: 19895632
references.citation: Genome Res. 2012 Dec;22(12):2339-55
references.pmid: 22899282