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| Status |
Public on Aug 15, 2013 |
| Title |
A Proneural to Mesenchymal Transition Mediated by NFkB Promotes Radiation Resistance in Glioblastoma (part 1) |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by array
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| Summary |
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.
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| Overall design |
Gene expression data for 17 isolated Glioma Stem Cells
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| Contributor(s) |
Bhat KL, Balasubramaniyan V, Vaillant B, Ezhilarasan R, Hummelink K, Hollingsworth F, Wani K, Heathcock L, James JD, Goodman LD, Conroy S, Long L, Lelic N, Wang S, Gumin J, Raj D, Kodama Y, Raghunathan A, Olar A, Joshi K, Pelloski CE, Heimberger A, Kim SH, Cahill DP, Rao G, denDunnen WA, Boddeke HM, Phillips HS, Nakano I, Lang FF, Colman H, Sulman EP, Aldape K |
| Citation(s) |
23993863 |
| Submission date |
Jul 24, 2013 |
| Last update date |
Jun 26, 2014 |
| Contact name |
Brian D Vaillant |
| Organization name |
Seton Brain and Spine Institute
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| Department |
Neurology
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| Street address |
1400 IH 35 Ste300
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| City |
Austin |
| State/province |
TX |
| ZIP/Postal code |
78701 |
| Country |
USA |
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| Platforms (1) |
| GPL17486 |
Affymetrix GeneChip Human Genome U133A 2.0 Array [CDF: HGU133A2_Hs_ENSG_16.0.0] |
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| Samples (17)
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| This SubSeries is part of SuperSeries: |
| GSE49009 |
A Proneural to Mesenchymal Transition Mediated by NFkB Promotes Radiation Resistance in Glioblastoma |
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| Relations |
| BioProject |
PRJNA213186 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE49161_RAW.tar |
45.8 Mb |
(http)(custom) |
TAR (of CEL) |
| Processed data included within Sample table |
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