Glioblastoma (GBM) is the most frequent and malignant form of primary brain tumor. GBM is essentially incurable and its resistance to therapy is attributed to a subpopulation of cells called glioma stem cells (GSCs). To meet the present shortage of relevant GBM cell (GC) lines we developed a library of annotated and validated cell lines derived from surgical samples of GBM patients, maintained under conditions to preserve GSC characteristics. This collection, which we call the Human Glioblastoma Cell Culture (HGCC) resource, consists of a biobank of 48 GC lines and an associated database containing high-resolution molecular data. We demonstrate that the HGCC lines are tumorigenic, harbor genomic lesions characteristic of GBMs, and represent all four transcriptional subtypes. The HGCC panel provides an open resource for in vitro and in vivo modeling of a large part of GBM diversity useful to both basic and translational GBM research.

Gliomas are primary brain tumors mainly affecting adults. The cellular origin is unknown. The recent identification of tumor-initiating cells in glioma, which share many similarities with normal neural stem cells, has suggested the cell of origin to be a transformed neural stem cell. In previous studies, using the RCAS/tv-a mouse model, platelet-derived growth factor B (PDGF-B)-induced gliomas have been generated from nestin or glial fibrillary acidic protein-expressing cells, markers of neural stem cells. To investigate if committed glial progenitor cells could be the cell of origin for glioma, we generated the Ctv-a mouse where tumor induction would be restricted to myelinating oligodendrocyte progenitor cells (OPCs) expressing 2 0 ,3 0 -cyclic nucleotide 3 0 -phosphodiesterase. We showed that PDGF-B transfer to OPCs could induce gliomas with an incidence of 33%. The majority of tumors resembled human WHO grade II oligodendroglioma based on close similarities in histopathology and expression of cellular markers. Thus, with the Ctv-a mouse we have showed that the cell of origin for glioma may be a committed glial progenitor cell.

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.

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