Abstract 510: A novel role for Olig2 in the regulation of glioma invasion

Abstract

Abstract Glioblastoma multiforme (GBM) are highly infiltrative, aggressive and lethal primary brain tumors in adults that are resistant to conventional treatments. A major clinical obstacle in the treatment of GBMs is the ability of glioma cells to invade the surrounding brain parenchyma, preventing their complete surgical resection. Several studies have shown that invasive glioma stem cells (GSCs) extend beyond the surgically resected regions. These invasive cells are the cause for tumor recurrence and poor prognosis in GBM patients. The molecular and cellular mechanism involved in the regulation of the switch from proliferation to invasion/migration in GBM is poorly understood. We investigated the role of Olig2, a Central Nervous System (CNS) specific transcription factor, in promoting the switch from proliferating to invading glioma cell. Genetically relevant murine glioma model as well as patient-derived glioma stem cells (GSCs) were utilized to identify the effect of Olig2 on glioma invasion. Functionally, Olig2-mediated invasion was assessed by 3D-transwell invasion assays, organotypic slice cultures as well as PDX tumors in immunocompromised mice. In addition, murine and patient-derived GSCs were utilized to identify direct genetic targets of Olig2 involved in glioma invasion by ChIP-seq and RNA-seq. Our data demonstrate that Olig2-expressing murine glioma stem/progenitor-like cells are highly invasive as compared to Olig2 knockout cells. We further corroborated the requirement of Olig2 for glioma invasion in patient-derived GSCs by utilizing shRNA-mediated knockdown of Olig2. Olig2 depletion resulted in reduced glioma cell invasion in at least four independent human GSCs. Recent studies have shown that activation of transcription factors such as Zeb1 and Twist1 occurs in invasive high grade gliomas. We show that knockdown of Olig2 in murine as well as human GSCs leads to a significant decrease in the expression of invasion genes such as Zeb1, Vimentin, Twist1, and Stat3 as compared to control cells. In conclusion, our studies highlight a novel role for the Olig2 signalling network in promoting the switch from proliferation to invasion in GBM, and provide a plausible target for inhibiting glioma invasion. Citation Format: Shiv K. Singh, Nicole Giannonatti, Robert Kupp, Costanza Lo Cascio, Shwetal Mehta. A novel role for Olig2 in the regulation of glioma invasion. [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 510. doi:10.1158/1538-7445.AM2015-510