CSIG-11OLIG2-MEDIATED REGULATION OF GLIOMA INVASION

Abstract

Glioblastoma multiforme (GBM) is a highly aggressive, infiltrative, and lethal brain tumor. GBM patients have an overall survival of <1 year, despite major research efforts in diagnosis and treatment. Almost all GBM patients experience tumor recurrence, for which there is currently no standard of care. A major challenge with GBM is that invasive glioma cells extend beyond the surgically resected regions typically defined based on magnetic resonance imaging. These invasive cells are resistant to adjuvant therapies, lead to tumor recurrence and contribute to poor prognosis in GBM patients. It has been proposed that migrating tumor cells undergo a switch from proliferation to invasion. However, the molecular and cellular mechanism involved in the regulation of this switch from proliferation to invasion/migration in GBM is poorly understood. We have previously shown that the lineage-specific transcription factor, Olig2 plays a critical role in glioma formation. Here we examined the differential role of Olig2 in promoting the switch from proliferation to invasion. We utilized genetically relevant mouse model of as well as GBM patient-derived xenograft (PDX) models to investigate the role of Olig2 in promoting glioma invasion. We show that Olig2 expressing glioma cells are highly invasive and migratory irrespective of their TCGA molecular subtype. Knockdown of Olig2 significantly decreases the ability of GBM PDX-derived cells to invade matrigel matrix. We find that Olig2 expressing cells are present both at the proliferating tumor core as well as at the invasive rim in GBM patient tissues. Mechanistically, we find that Olig2 regulates the expression of epithelial-to-mesenchymal transition (EMT) genes such as Twist1, Snai1, Zeb1, Stat3, CD44 and Vimentin and genes involved in invasion regulation like TGFβ2 and Epha2. Our data provides evidence for a role of Olig2 in both proliferation and invasion.