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 journalArticlepeer-review

729 Citations (Scopus)


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
Pages (from-to)331-346
Number of pages16
JournalCancer Cell
Issue number3
Publication statusPublished - 2013 Sept 9

Bibliographical note

Funding Information:
We would like to acknowledge the Caroline Ross Endowment Fellowship, the American Brain Tumor Association Basic Research Fellowship, the Odyssey Special Fellowship, and the MDACC Brain Tumor SPORE Career Development grant (to K.P.L.B.); the Brain Tumor Funders’ Collaborative, the Dr. Marnie Rose Foundation, and the National Brain Tumor Society (to K.A.); the V Foundation and SPORE grant P50CA127001 from NIH/NCI (to K.A. and H.C.); the Huntsman Cancer Foundation (to H.C.); the Ben and Cathy Ivy Foundation Research Award (to F.F.L., K.A., and E.P.S.); the SPORE Animal Core grant (to F.F.L.); grant R01-CA1208113 from NIH/NCI (to A.H.); and Dutch Cancer Society grant RUG 2011-5150 (to V.B., H.W.B., and W.F.D.) for their generous support. We thank Alicia Ledoux, Bhavna Singh, and Susan Cweren for histology; Verlene Henry for animal injections; and the Flow Cytometry & Cellular Imaging Core Facility, Small Animal Imaging Facility, and the Division of Surgery Pathology Core Facility (all at MDACC supported by P30-CA016672) for technical support. We apologize for not citing some original references because of space limitations. H.S.P. is an employee and stockholder of Roche/Genentech.

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research


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