Cancer Cell
Volume 24, Issue 3, 9 September 2013, Pages 331-346
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Article
Mesenchymal Differentiation Mediated by NF-κB Promotes Radiation Resistance in Glioblastoma

https://doi.org/10.1016/j.ccr.2013.08.001Get rights and content
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Highlights

  • Patient-derived GSCs differ in their molecular features compared to the parental GBM

  • PN GSCs undergo differentiation to a MES state in a TNF-α/NF-κB-dependent manner

  • Macrophages/microglia infiltration correlates with the MES signature in human GBM

  • NFκB activation, MES state, and CD44 levels associate with radio resistance in GBM

Summary

Despite extensive study, few therapeutic targets have been identified for glioblastoma (GBM). Here we show that patient-derived glioma sphere cultures (GSCs) that resemble either the proneural (PN) or mesenchymal (MES) transcriptomal subtypes differ significantly in their biological characteristics. Moreover, we found that a subset of the PN GSCs undergoes differentiation to a MES state in a TNF-α/NF-κB-dependent manner with an associated enrichment of CD44 subpopulations and radioresistant phenotypes. We present data to suggest that the tumor microenvironment cell types such as macrophages/microglia may play an integral role in this process. We further show that the MES signature, CD44 expression, and NF-κB activation correlate with poor radiation response and shorter survival in patients with GBM.

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16

These authors contributed equally to this work

17

These authors contributed equally to this work