Mesenchymal Differentiation Mediated by NF-κB Promotes Radiation Resistance in Glioblastoma

• 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

SummaryDespite 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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