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 (mGC1) that are less resistant to cancer drugs, compared with those originating from more differentiated nestin- (mGC2) or 2,'3'-cyclic nucleotide 3'-phosphodiesterase (mGC3)-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 mGC1 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.

LGR5 promotes tumorigenicity and invasion of glioblastoma stem‐like cells and is a potential therapeutic target for a subset of glioblastoma patients

“…LGR5 gene expression was analyzed in 60 patient‐derived GSC cultures that had been reclassified ; ordered based on LGR5 expression; and divided by quartiles into LGR5 low , LGR5 intermediate , and LGR5 high groups (Figure A). In line with previous data (196 TCGA GBM samples classified into four subtypes ), LGR5 was significantly higher in proneural GSCs (Figure B), which was validated by RT‐qPCR for the majority of samples (Figure C).…”

“…To identify biomarkers for LGR5‐regulated GSC cultures, we used our microarray data and compared gene expression between the LGR5 high and LGR5 low cultures. We collected published gene lists, including WNT pathway and target genes , receptor tyrosine kinase signaling genes , genes involved in glioma development , GSC markers and MCO genes , and these 758 glioma‐ and LGR5‐relevant genes (see supplementary material, Table S1) were compared for their average expression in the LGR5 high and LGR5 low cultures (Welch's two sample t ‐test, p < 0.05), which produced a list of 164 genes (see supplementary material, Table S2). The top four genes were selected, and their expression analyzed in LGR5 high ‐ELDA high and LGR5 high ‐ELDA low GSC cultures (Figure A), which showed a significant difference for LPAR4 , CCND2 , and OLIG2 .…”

“…All GSC cultures were derived from anonymized grade IV, nonrecurrent glioblastoma samples obtained from patients undergoing surgical resection at Uppsala University Hospital in accordance with protocols approved by the regional ethical review board (2007/353) and following patients' written consent . Sixty IDH1 wild‐type cultures were used at passages 5–15 and were tested negative for mycoplasma using two different methods, MycoAlert Mycoplasma Detection kit (Lonza, Basel, Switzerland) and a PCR‐based method as previously described .…”

“…We recently demonstrated that the cell of origin could influence the phenotype of GBM cells , where a stem cell‐like origin produced GSCs that were more malignant and more sensitive to drugs than a more differentiated precursor cell origin. Furthermore, we identified a mouse cell origin (MCO) gene signature that could be used to stratify patient‐derived GSCs into functionally distinct groups.…”

“…High LGR5 expression has also been connected with high OLIG2 expression and the proneural subtype . To further understand the role of LGR5 in GBM, we have studied its expression and function in our large resource of characterized patient‐derived GSC cultures .…”