Year: 2016
Type: conference-abstract
Abstract: 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 CD44 and FZD6, an inhibitor of canonical Wnt signaling. Methylation analysis shows Wnt signaling is also regulated at the epigenetic level, given the subtype-dependent methylation pattern of pathway genes. Finally, we identify a significant inverse relationship between canonical Wnt signaling and the T-cell signature, suggesting the role of the Wnt pathway in regulating immune response and the tumor microenvironment. Our results reveal the clinical significance of Wnt signaling in predicting glioma subtype, radiation response, and patient survival. These exciting results reveal potential therapeutic options in treating aggressive tumors and targeting cancer stem cells in a more personalized-medicine approach.
Source: Neuro-Oncology
Language: English
Subfield: Genetics
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2586815623