Abstract Glioblastomas (GBMs) maintain their cellular heterogeneity with glioma stem cells (GSCs) producing a variety of tumor cell types. Here, we interrogated the oncogenic roles of Lim domain only 2 (LMO2) in GBM and GSCs in mice and human. High expression of LMO2 was found in human patient-derived GSCs compared to the differentiated progeny cells. LMO2 is required for GSC growth both in vitro and in vivo, as shRNA-mediated LMO2 silencing attenuated tumor growth derived from human GSCs. Further, LMO2 is sufficient to induce stem cell characteristics (stemness) in mouse pre-malignant astrocytes, as forced LMO2 expression facilitated in vitro and in vivo growth of astrocytes derived from Ink4a/Arf null mice and acquisition of GSC phenotypes. A subset of mouse and human GSCs converted into vascular endothelial-like tumor cells both in vitro and in vivo, which phenotype was attenuated by LMO2 silencing and promoted by LMO2 overexpression. Mechanistically, the action of LMO2 for induction of glioma stemness is mediated by transcriptional regulation of Jagged1 resulting in activation of the Notch pathway, whereas LMO2 directly occupies the promoter regions of the VE-cadherin gene for a gain of endothelial cellular phenotype. Subsequently, selective ablation of human GSC-derived VE-cadherin-expressing cells attenuated vascular formation in mouse intracranial tumors, thereby significantly prolonging mouse survival. Clinically, LMO2 expression was elevated in GBM tissues and inversely correlated with prognosis of GBM patients. Taken together, our findings describe novel dual roles of LMO2 to induce tumorigenesis and angiogenesis, and provide potential therapeutic targets in MGs. Citation Format: Sunghak Kim, Eun-Jung Kim, Park Cheol Gyu, Se-Yeong Oh, Minata Mutsuko, Hyunggee Kim, Ichiro Nakano. A hematopoietic stem cell factor drives brain tumor initiating cell genesis through Notch signaling. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2321. doi:10.1158/1538-7445.AM2015-2321

Abstract Glioma stem cells (GSCs), which reside within the perivascular niche (PVN) to maintain self-renewal capacity, are responsible for glioblastoma initiation, progression, and recurrence. However, the molecular mechanisms controlling GSCs and endothelial cells in the PVN are poorly understood. Here, we report that PDGF-driven activation of nitric oxide (NO) synthase increases NO-dependent ID4 expression, which promotes Jagged-Notch activity through miR-129 suppression in GSCs and endothelial cells. ID4 also increases PDGF-PDGFR signaling in a direct or miR-129-dependent manner, which drives the PDGFR-NO-ID4 signaling in GSCs and endothelial cells. This signaling circuit promotes tumor progression along with increased GSC self-renewal and growth of tumor vasculature in the PVN, which is dramatically suppressed by Notch inhibitor. ID4 levels correlate positively with NOS2, Hes1, and Hey1 and negatively with miR-129 in primary GSCs. Thus, targeting the PDGFR-NO-ID4 signaling circuit and Notch activity in the PVN might serve as an efficacious therapeutic modality for glioblastoma. Citation Format: Hye-Min Jeon, Hyunggee Kim. PDGFR-ID4-Notch axis is a common signaling pathway activated in glioma stem cells and endothelial cells. [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 B34.