HG-98: IDENTIFICATION OF THE PRE-MALIGNANT CELL OF ORIGIN IN PEDIATRIC GLIOBLASTOMA MULTIFORME

One of the major difficulties in identifying the cell of origin for pediatric glioblastoma is the complex cellular composition of this disease. It is now hypothesized that cell of origin for high-grade glioma resides within the progenitor populations. While pediatric glioblastoma has been shown to be genetically distinct from adult glioblastoma it is unclear whether their cell of origin are also different. To identify the cell of origin we first delineated the cellular hierarchy in human brain development. After a functional high throughput screen, CD15, Notch1, EGFR, and CD90 in various combinations identified long-term self-renewing multi-potent neural stem cells (NSCs) from multi-potent progenitors with limited self-renewal capacity (NPC) from human fetal, pediatric and adult Brain. In surgical human glioblastoma samples (adult and pediatric) in-vivo tumor initiating and self-renewing cells were isolated from the progenitor cells and not in the neural stem cells. Interestingly we did observe a small frequency of NSC cells forming distinct lesions in the brain, which on further analysis showed the presence of both the NSC and NPC populations where as the tumor initiating population did not show the presence of the NSC but only tumor initiating NPCs. Taken together our data suggests the presence of “normal” or pre-malignant stem cells in glioblastoma. Targeted sequencing of known mutations identified the genomic events which can distinguish these pre-malignant neural stem cells from the tumor initiating cancer stem cells. This suggests a common cell of origin for pediatric and adult glioblastoma with distinct genomic mutations.