Abstract A11: Identification of the premalignant cell of origin in human glioblastoma multiforme

One of the major difficulties in identifying the cell of origin for glioblastoma is the complex cellular composition of this disease. It is now hypothesized that the different subtypes of high-grade glioma may have different cell of origin and in mouse models it has been shown that the cell of origin resides within the progenitor populations. To identify the human cell of origin we delineated the stages of CNS stem cell differentiation in fetal and adult human brain. After a functional high throughput screen, we identified a panel of four antibodies (i.e CD15, Notch1, EGFR, and CD90) that in various combinations can separate long-term self-renewing multi-potent neural stem cells (NSCs) from multi-potent progenitors with limited self-renewal capacity (NPC) from non-neoplastic human fetal and adult Brain (sub-ventricular zone). FACS sorted cells were analyzed for single cell lineage multi-potentiality, lineage bias and self-renewal to trace and characterize their lineage relationships. In surgical human glioblastoma samples, however we observed in-vivo tumor initiating and in-vitro tumorsphere-forming frequency was predominant in 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, whereas the tumor initiating enriched 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, RNAseq and 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. These pre-malignant cells could comprise a cellular reservoir that may need to be targeted to prevent tumor relapse. Citation Format: Siddhartha S. Mitra, Sharareh Gholamin, Rahul Sinha, Rachel M. Morganti, Irving Weissman, Samuel H. Cheshier. Identification of the premalignant cell of origin in human glioblastoma multiforme. [abstract]. In: Proceedings of the AACR Special Conference: Advances in Brain Cancer Research; May 27-30, 2015; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2015;75(23 Suppl):Abstract nr A11.