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E-GEOD-49162 - A Proneural to Mesenchymal Transition Mediated by NFkB Promotes Radiation Resistance in Glioblastoma (part 2)

Status
Released on 15 August 2013, last updated on 27 August 2013
Organism
Homo sapiens
Samples (4)
Array (1)
Protocols (7)
Description
SUMMARY Despite numerous genome-wide association studies involving glioblastoma (GBM), few therapeutic targets have been identified for this disease. Using patient derived glioma sphere cultures (GSCs), we have found that a subset of the proneural (PN) GSCs undergo transition to a mesenchymal (MES) state in a TNFa/NFkB dependent manner with an associated enrichment of CD44 sub-populations and radio-resistant phenotypes. To the contrary, MES GSCs exhibit constitutive NFkB activation, CD44 enrichment and radio-resistance. Patients whose tumors exhibit a higher MES metagene, increased expression of CD44, or activated NFkB were associated with poor radiation response and shorter survival. Our results indicate that NFkB activation mediated MES differentiation and radiation resistance presents an attractive therapeutic target for GBM. SIGNIFICANCE In this study, we show plasticity between the proneural (PN) and mesenchymal (MES) transcriptome signatures observed in glioblastoma (GBM). Specifically, we show that PN glioma sphere cultures (GSCs) can be induced to a MES state with an associated enrichment of CD44 expressing cells and a gain of radio-resistance, which we implicate as NFkB- dependent. Newly diagnosed GBM samples show a direct correlation between radiation response, higher MES metagene, CD44 expression, and NFkB activation. This correlation is also observed in the subset of GBM samples that do not exhibit IDH1 mutation, a favorable prognostic marker. Our results uncover a previously unknown link between subtype plasticity that is regulated by NFkB. Inhibition of NFkB activation can directly impact radio-resistance and presents an attractive therapeutic target for GBM. 4 treatments
Experiment type
transcription profiling by array 
Contacts
Brian D Vaillant <geo@ncbi.nlm.nih.gov>, Aditya Raghunathan, Adriana Olar, Amy Heimberger, Brian Vaillant, Christopher E Pelloski, Daniel P Cahill, Divya Raj, Erik P Sulman, Faith Hollingsworth, Frederick F Lang, Ganesh Rao, Heidi S Phillips, Hendrikus M Boddeke, Howard Colman, Ichiro Nakano, Johanna D James, Joy Gumin, Karlijn Hummelink, Kaushal Joshi, Kenneth Aldape, Khalida Wani, Krishna L Bhat, Lihong Long, Lindsey D Goodman, Lindsey Heathcock, Nina Lelic, Ravesanker Ezhilarasan, Se H Kim, Siobhan Conroy, Suzhen Wang, Veerakumar Balasubramaniyan, Wilfred A denDunnen, Yoshinori Kodama
MIAME
PlatformsProtocolsVariablesProcessedRaw
Files
Investigation descriptionE-GEOD-49162.idf.txt
Sample and data relationshipE-GEOD-49162.sdrf.txt
Raw data (1)E-GEOD-49162.raw.1.zip
Processed data (1)E-GEOD-49162.processed.1.zip
Array designA-GEOD-17486.adf.txt
Links