TMIC-16. CORE-LIKE TUMOR CELLS PROMOTE MALIGNANCE OF GLIOBLASTOMA VIA INTERCELLULAR CROSSTALK WITH EDGE-LIKE TUMOR CELLS IN A HDAC1-CD109 DEPENDENT MANNER

Abstract Glioblastoma (GBM) is a malignant primary brain cancer without cure, due to the edge infiltrating tumor cells and non-complete resection. Although intratumoral heterogeneity is recognized in various cancers including GBM, its spatial distribution and intercellular crosstalk remain poorly understood. Previously, we identified two mutually exclusive glioma stem-like cells (GSCs) subtypes in GBM, termed mesenchymal (MES) and non-MES GSCs. Here, we tested the hypothesis that non-MES and MES GSCs have inter-cellular crosstalk to promote GBM aggressiveness and heterogeneity. We found that MES GSCs are preferentially located in the tumor core region, while non-MES GSCs subside in the tumor edge. Co-culture with MES GSC-containing cultures (glioma spheres) promoted both in vitro growth and in vivo tumorigenicity of non-MES ones. By a high throughput screening, several HDAC inhibitors selectively eliminated MES glioma spheres, while preserving non-MES glioma spheres. Among the HDAC family, HDAC1 is upregulated in GBM and associated with unfavorable outcome. Knockdown of HDAC1 blocked the intercellular pro-tumorigenic signal from MES glioma spheres to the non-MES counterparts. Mechanistically, CD109 is secreted from MES glioma spheres, thereby contributing intercellular pro-tumorigenic signals from MES to non-MES spheres. By RNA sequence, we found that HDAC1 regulates transcriptional activity of CD109 via binding to the promoter of CD109 together with the MES-specific transcription factor C/EBPb. To validate the intercellular signals in a single tumor, we established 6 clones of spheres from both tumor core and edge derived from the same GBM patient. The core lines contained those with higher resistance to irradiation (IR) treatment in comparison to the edge-derived counterparts. Furthermore, the core glioma spheres that showed higher MES signature promoted the growth and transformation of the non-MES like edge-derived glioma spheres both in vitro and in vivo. Collectively, our data identified HDAC1-CD109 dependent intercellular crosstalk from core like MES GCSs to edge like non-MES GSCs.