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

Krishna P.L. Bhat, Veerakumar Balasubramaniyan, Brian Vaillant, Ravesanker Ezhilarasan, Karlijn Hummelink, Faith Hollingsworth, Khalida Wani, Lindsey Heathcock, Johanna D. James, Lindsey D. Goodman, Siobhan Conroy, Lihong Long, Nina Lelic, Suzhen Wang, Joy Gumin, Divya Raj, Yoshinori Kodama, Aditya Raghunathan, Adriana Olar, Kaushal JoshiChristopher E. Pelloski, Amy Heimberger, Se Hoon Kim, Daniel P. Cahill, Ganesh Rao, Wilfred F.A. DenDunnen, Hendrikus W.G.M. Boddeke, Heidi S. Phillips, Ichiro Nakano, Frederick F. Lang, Howard Colman, Erik P. Sulman, Kenneth Aldape

Research output: Contribution to journalArticle

448 Scopus citations

Abstract

Despite extensive study, few therapeutic targets have been identified for glioblastoma (GBM). Here weshow 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.

Original languageEnglish (US)
Pages (from-to)331-346
Number of pages16
JournalCancer cell
Volume24
Issue number3
DOIs
StatePublished - Sep 9 2013

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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    Bhat, K. P. L., Balasubramaniyan, V., Vaillant, B., Ezhilarasan, R., Hummelink, K., Hollingsworth, F., Wani, K., Heathcock, L., James, J. D., Goodman, L. D., Conroy, S., Long, L., Lelic, N., Wang, S., Gumin, J., Raj, D., Kodama, Y., Raghunathan, A., Olar, A., ... Aldape, K. (2013). Mesenchymal Differentiation Mediated by NF-κB Promotes Radiation Resistance in Glioblastoma. Cancer cell, 24(3), 331-346. https://doi.org/10.1016/j.ccr.2013.08.001