Abstract 141: HEY1-mediated inhibition of glioma stem cell proliferation is associated with restoration of glioma stem cell division asymmetry and transcriptional repression of PDGFRA

Abstract

Abstract Emerging evidence suggests that deregulation of cell-fate regulatory mechanisms in subpopulations of stem-like tumor cells can contribute to the initiation, progression, and recurrence of glioma. In this study, we report that Hey1 expression suppresses the expansion of oligodendroglial progenitor (OPC)-like glioma stem cells, which are a putative cell of origin for high-grade gliomas. We found that Hey1 expression reduced the proliferation of primary neural progenitor cells isolated from mice without the tumor suppressor Tp53, and OPC-like glioma stem cell cultures isolated from a mouse model of glioma driven by an EGFR gain-of-function mutation and Tp53 loss (v-ErbB/p53-/-). Further analysis of these cultures revealed that Hey1-mediated reductions in proliferation were associated with suppression of self-renewal and a reduced percentage of symmetric cell divisions. Mechanistically, we found that HEY1 directly bound to novel promoter elements and repressed the mRNA expression of a key marker and mitogenic driver of OPCs, the PDGF Receptor A (Pdgfra). Furthermore, Hey1-mediated of Pdgfra expression was associated with inactivation of the canonical PDGF/PDGFRA downstream target, extracellular signal-regulated kinases (ERK), in v-ErbB/p53-/- glioma stem-like cells. Key findings made in the murine system were validated in patient-derived glioma stem-like cells. Moreover, analyzing publicly available databases, we found that the subset of glioma patients with high levels of HEY1 expression had improved survival compared to patients with tumors expressing low levels of HEY1. Further supporting a role for HEY1 in the regulation of the oligodendroglial lineage, ontologic analysis revealed that the subset of patients with high levels of HEY1 expression were also characterized by the expression of gene sets associated with oligodendroglial differentiation. These cellular, molecular and genetic findings provide support for a model in which HEY1 functions to suppress glioma progression by inhibiting the expansion of glioma stem cells. Citation Format: Damian A. Almiron Bonnin, Jaclyn Sullivan, Mark A. Israel, Matthew Havrda C. Havrda. HEY1-mediated inhibition of glioma stem cell proliferation is associated with restoration of glioma stem cell division asymmetry and transcriptional repression of PDGFRA [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 141.