STMC-35. DIVERGENT Wnt SIGNALING REGULATES GLIOMA STEM CELLS AND TUMOR PHENOTYPE

Glioblastomas (GBMs), the most aggressive adult brain tumor, can be classified into clinically relevant subtypes based on gene expression and genomic alterations that influence survival and treatment response. Additionally, glioma stem cells (GSCs) are recognized as unique subpopulations that contribute to tumorigenesis, recurrence, and therapy resistance. Because Wnt signaling is critical in neural stem cell growth, we hypothesized the Wnt pathway would regulate GSCs and glioma subtypes. We have characterized two distinct subtypes of GSCs, proneural (PN) and mesenchymal (MES), by gene expression profiling, in vitro growth, and radiation response. Subsequent analysis of differentially expressed transcripts between GSCs and patient glioma subtypes identified activators of the canonical Wnt pathway enriched in the proneural subtype, while inhibitors are up-regulated in the mesenchymal. Wnt signaling genes predicted radiation resistance and were prognostic factors for patient survival, with high canonical Wnt signaling predictive of prolonged survival. We validated these results in multiple independent data sets, including TCGA glioma patient data. To further investigate the relationship between Wnt signaling, tumor subtype, and malignancy, we measured protein expression and genome-wide methylation using a panel of subtyped GSCs. Proneural GSCs expressed higher levels of s9-phosphorylated GSK3β and transcription factor Sox2, while mesenchymal GSCs had greater expression of ...

Source: Neuro-Oncology - November 6, 2016 Category: Cancer & Oncology Authors: Alvarez, A., Huang, T., Pangeni, R., Lu, S., Brennan, C., Sulman, E., Lu, X., Nakano, I., Zhang, W., Zhang, Z., Hu, B., Cheng, S.-Y. Tags: STEM CELLS Source Type: research