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

By K. Bhat, V. Balasubramaniyan, B. Vaillant, R. Ezhilarasan, K. Hummelink, F. Hollingsworth, K. Wani, L. Heathcock, Johanna D. James, Lindsey D. Goodman and 23 more. Cancer Cell, 2013

1,058 citations recorded by the source corpus.

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 undergo differentiation to a MES state in a TNFα/NF-κB dependent manner with an associated enrichment of CD44 subpopulations and radio-resistant 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.

Subfields: Genetics, Immunology, Neurology

View Paper: https://www.semanticscholar.org/paper/73980ffddb5c53b63fb40574e6c96fb494cbe594

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In Genetics

1. J. Lathia
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In Immunology

1. Aviv Regev
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In Neurology

1. R. DePinho

Citations in the corpus

• NF-κB, an Active Player in Human Cancers (2014, positive): “A recent study showed that NF-κ B activation is linked to mesenchymal differentiation of glioblastoma, and enhanced resistance to radiation therapy (66).”
• Cancer stem cells in glioblastoma (2015, background): “…resistance of CSCs to cytotoxic therapies, including the DNA damage checkpoint, Notch, NF-κB, EZH2, and PARP (Bao et al. 2006a; Wang et al. 2010; Bhat et al. 2013; Venere et al. 2014; Kim et al. 2015), which suggests that CSCs develop multiplemechanisms of resistance thatmay require…”
• Single-cell RNA-seq highlights intratumoral heterogeneity in primary glioblastoma (2014, background): “These tumors contain cellular niches enriched for distinct phenotypic properties, including transient quiescence and self-renewal (14–16), adaptation to hypoxia (17), and resistance to radiation induced DNA damage (18, 19).”
• Glioblastoma: pathology, molecular mechanisms and markers (2015, background): “Indeed, subclass assignment has been shown to be unstable and change following surgical resection and radiochemotherapy [14, 129].”
• Tumor evolution of glioma intrinsic gene expression subtype associates with immunological changes in the microenvironment (2017, background): “, 2015), have been proposed as regulators of PN-to-MES transition through nuclear factor kB activation (Bhat et al., 2013) and may provide growth factormediated proliferative signals which could be therapeutically targeted (Patel et al.”