Glioblastoma Cell Malignancy and Drug Sensitivity Are Affected by the Cell of Origin

Cell Rep. 2017 Jan 24;18(4):977-990. doi: 10.1016/j.celrep.2017.01.003.


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 mGC1GFAP cells were also significantly more self-renewing, tumorigenic, and sensitive to cancer drugs compared with those that clustered with mouse GCs of more differentiated origin.

Keywords: cancer stem cell; cell of origin; central nervous system; drug response; glioblastoma; glioma; mouse model; neural stem cell; oligodendrocyte precursor cell; self-renewal.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 2',3'-Cyclic-Nucleotide Phosphodiesterases / genetics
  • 2',3'-Cyclic-Nucleotide Phosphodiesterases / metabolism
  • Adult
  • Aged
  • Animals
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use
  • Brain / cytology
  • Brain / metabolism
  • Brain / pathology
  • Brain Neoplasms / drug therapy
  • Brain Neoplasms / mortality
  • Brain Neoplasms / pathology*
  • Cell Differentiation
  • Cell Proliferation / drug effects
  • Cell Self Renewal
  • Cell Survival / drug effects
  • Cyclin-Dependent Kinase Inhibitor p19 / deficiency
  • Cyclin-Dependent Kinase Inhibitor p19 / genetics
  • Disease-Free Survival
  • Female
  • Glial Fibrillary Acidic Protein / genetics
  • Glial Fibrillary Acidic Protein / metabolism
  • Glioblastoma / drug therapy
  • Glioblastoma / mortality
  • Glioblastoma / pathology*
  • Humans
  • Male
  • Mice
  • Mice, Inbred NOD
  • Mice, Knockout
  • Mice, SCID
  • Middle Aged
  • Nestin / genetics
  • Nestin / metabolism
  • Tumor Cells, Cultured


  • Antineoplastic Agents
  • Cyclin-Dependent Kinase Inhibitor p19
  • Glial Fibrillary Acidic Protein
  • Nestin
  • 2',3'-Cyclic-Nucleotide Phosphodiesterases