title: Glioblastoma Cell Malignancy and Drug Sensitivity Are Affected by the Cell of Origin.
abstract: The identity of the glioblastoma (GBM) cell of origin and its contributions to disease progression and treatment response remain largely unknown. We have analyzed how the phenotypic state of the initially transformed cell affects mouse GBM development and essential GBM cell (GC) properties. We find that GBM induced in neural stem-cell-like glial fibrillary acidic protein (GFAP)-expressing cells in the subventricular zone of adult mice shows accelerated tumor development and produces more malignant GCs (mGC1GFAP) that are less resistant to cancer drugs, compared with those originating from more differentiated nestin- (mGC2NES) or 2,'3'-cyclic nucleotide 3'-phosphodiesterase (mGC3CNP)-expressing cells. Transcriptome analysis of mouse GCs identified a 196 mouse cell origin (MCO) gene signature that was used to partition 61 patient-derived GC lines. Human GC lines that clustered with the mGC1GFAPcells were also significantly more self-renewing, tumorigenic, and sensitive to cancer drugs compared with those that clustered with mouse GCs of more differentiated origin.
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, 75185 Uppsala, Sweden.
authors.forename: Yiwen
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, 75185 Uppsala, Sweden.
authors.forename: Voichita Dana
authors.initials: VD
authors.lastname: Marinescu
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, 75185 Uppsala, Sweden.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Xie
authors.affiliation: Department of Medical Sciences, Cancer Pharmacology and Computational Medicine, Uppsala University, 75185 Uppsala, Sweden.
authors.forename: Malin
authors.initials: M
authors.lastname: Jarvius
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, 75185 Uppsala, Sweden.
authors.forename: Naga Prathyusha
authors.initials: NP
authors.lastname: Maturi
authors.affiliation: Department of Medical Sciences, Cancer Pharmacology and Computational Medicine, Uppsala University, 75185 Uppsala, Sweden.
authors.forename: Caroline
authors.initials: C
authors.lastname: Haglund
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, 75185 Uppsala, Sweden.
authors.forename: Sara
authors.initials: S
authors.lastname: Olofsson
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, 75185 Uppsala, Sweden.
authors.forename: Nanna
authors.initials: N
authors.lastname: Lindberg
authors.affiliation: Department of Forensic Medicine, The National Board of Forensic Medicine, Box 1024, 75140 Uppsala, Sweden.
authors.forename: Tommie
authors.initials: T
authors.lastname: Olofsson
authors.affiliation: Department of Neuroscience, Uppsala University, Uppsala University Hospital, 75185 Uppsala, Sweden.
authors.forename: Caroline
authors.initials: C
authors.lastname: Leijonmarck
authors.affiliation: Department of Neuroscience, Uppsala University, Uppsala University Hospital, 75185 Uppsala, Sweden.
authors.forename: Göran
authors.initials: G
authors.lastname: Hesselager
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, 75185 Uppsala, Sweden.
authors.forename: Irina
authors.initials: I
authors.lastname: Alafuzoff
authors.affiliation: Department of Medical Sciences, Cancer Pharmacology and Computational Medicine, Uppsala University, 75185 Uppsala, Sweden.
authors.forename: Mårten
authors.initials: M
authors.lastname: Fryknäs
authors.affiliation: Department of Medical Sciences, Cancer Pharmacology and Computational Medicine, Uppsala University, 75185 Uppsala, Sweden.
authors.forename: Rolf
authors.initials: R
authors.lastname: Larsson
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, 75185 Uppsala, Sweden. Electronic address: sven.nelander@igp.uu.se.
authors.forename: Sven
authors.initials: S
authors.lastname: Nelander
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, 75185 Uppsala, Sweden. Electronic address: lene.uhrbom@igp.uu.se.
authors.forename: Lene
authors.initials: L
authors.lastname: Uhrbom
mesh_terms: D015087:2',3'-Cyclic-Nucleotide Phosphodiesterases / Q000235:genetics / Q000378:metabolism; D000328:Adult; D000368:Aged; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D001921:Brain / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D001932:Brain Neoplasms / Q000188:drug therapy / Q000401:mortality / Q000473:pathology*; D002454:Cell Differentiation; D049109:Cell Proliferation / Q000187:drug effects; D000066673:Cell Self Renewal; D002470:Cell Survival / Q000187:drug effects; D050764:Cyclin-Dependent Kinase Inhibitor p19 / Q000172:deficiency / Q000235:genetics; D018572:Disease-Free Survival; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics / Q000378:metabolism; D005909:Glioblastoma / Q000188:drug therapy / Q000401:mortality / Q000473:pathology*; D006801:Humans; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D008875:Middle Aged; D064231:Nestin / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D050764:Cyclin-Dependent Kinase Inhibitor p19; D005904:Glial Fibrillary Acidic Protein; D064231:Nestin; D015087:2',3'-Cyclic-Nucleotide Phosphodiesterases
keywords: cancer stem cell; cell of origin; central nervous system; drug response; glioblastoma; glioma; mouse model; neural stem cell; oligodendrocyte precursor cell; self-renewal