title: Mesenchymal differentiation mediated by NF-κB promotes radiation resistance in glioblastoma.
abstract: 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.
authors.affiliation: Department of Pathology, The University of Texas, M.D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Krishna P L
authors.initials: KPL
authors.lastname: Bhat
authors.affiliation: Department of Neuroscience, University of Groningen, University Medical Center Groningen, Groningen, 9713 AV, The Netherlands.
authors.forename: Veerakumar
authors.initials: V
authors.lastname: Balasubramaniyan
authors.affiliation: Seton Brain and Spine Institute, Austin, TX 78701, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Vaillant
authors.affiliation: Department of Radiation Oncology, The University of Texas, M.D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Ravesanker
authors.initials: R
authors.lastname: Ezhilarasan
authors.affiliation: Department of Pathology, The University of Texas, M.D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Karlijn
authors.initials: K
authors.lastname: Hummelink
authors.affiliation: Department of Pathology, The University of Texas, M.D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Faith
authors.initials: F
authors.lastname: Hollingsworth
authors.affiliation: Department of Pathology, The University of Texas, M.D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Khalida
authors.initials: K
authors.lastname: Wani
authors.affiliation: Department of Pathology, The University of Texas, M.D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Lindsey
authors.initials: L
authors.lastname: Heathcock
authors.affiliation: Department of Pathology, The University of Texas, M.D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Johanna D
authors.initials: JD
authors.lastname: James
authors.affiliation: Department of Radiation Oncology, The University of Texas, M.D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Lindsey D
authors.initials: LD
authors.lastname: Goodman
authors.affiliation: Department of Neuroscience, University of Groningen, University Medical Center Groningen, Groningen, 9713 AV, The Netherlands.
authors.forename: Siobhan
authors.initials: S
authors.lastname: Conroy
authors.affiliation: Department of Pathology, The University of Texas, M.D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Lihong
authors.initials: L
authors.lastname: Long
authors.affiliation: Deparment of Neurosurgery, Massachusetts General Hospital/Brain Tumor Center, Boston, MA 02114, USA.
authors.forename: Nina
authors.initials: N
authors.lastname: Lelic
authors.affiliation: Department of Neuro-oncology, The University of Texas, M.D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Suzhen
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Neurosurgery, The University of Texas, M.D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Joy
authors.initials: J
authors.lastname: Gumin
authors.affiliation: Department of Neuroscience, University of Groningen, University Medical Center Groningen, Groningen, 9713 AV, The Netherlands.
authors.forename: Divya
authors.initials: D
authors.lastname: Raj
authors.affiliation: Division of Pathology, Osaka National Hospital, National Hospital Organization, Chuo-ku, Osaka 540-0006, Japan.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Kodama
authors.affiliation: Department of Pathology, Henry Ford Hospital, Detroit, MI, 48202, USA.
authors.forename: Aditya
authors.initials: A
authors.lastname: Raghunathan
authors.affiliation: Department of Pathology, The University of Texas, M.D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Adriana
authors.initials: A
authors.lastname: Olar
authors.affiliation: Department of Neurosurgery, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Kaushal
authors.initials: K
authors.lastname: Joshi
authors.affiliation: Department of Radiation Oncology, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Pelloski
authors.affiliation: Department of Neurosurgery, The University of Texas, M.D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Amy
authors.initials: A
authors.lastname: Heimberger
authors.affiliation: Department of Pathology, Yonsei University College of Medicine, Seoul, 120-752, Korea.
authors.forename: Se Hoon
authors.initials: SH
authors.lastname: Kim
authors.affiliation: Deparment of Neurosurgery, Massachusetts General Hospital/Brain Tumor Center, Boston, MA 02114, USA.
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Cahill
authors.affiliation: Department of Neurosurgery, The University of Texas, M.D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Ganesh
authors.initials: G
authors.lastname: Rao
authors.affiliation: Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, 9700 RB, The Netherlands.
authors.forename: Wilfred F A
authors.initials: WFA
authors.lastname: Den Dunnen
authors.affiliation: Department of Neuroscience, University of Groningen, University Medical Center Groningen, Groningen, 9713 AV, The Netherlands.
authors.forename: Hendrikus W G M
authors.initials: HWGM
authors.lastname: Boddeke
authors.affiliation: Department of Tumor Biology and Angiogenesis, Genentech, Inc., South San Francisco, CA 94080, USA.
authors.forename: Heidi S
authors.initials: HS
authors.lastname: Phillips
authors.affiliation: Department of Neurosurgery, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Ichiro
authors.initials: I
authors.lastname: Nakano
authors.affiliation: Department of Neurosurgery, The University of Texas, M.D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Frederick F
authors.initials: FF
authors.lastname: Lang
authors.affiliation: Department of Neurosurgery, and Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84132, USA.
authors.forename: Howard
authors.initials: H
authors.lastname: Colman
authors.affiliation: Department of Radiation Oncology, The University of Texas, M.D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Erik P
authors.initials: EP
authors.lastname: Sulman
authors.affiliation: Department of Pathology, The University of Texas, M.D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Aldape
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics; D016000:Cluster Analysis; D019175:DNA Methylation; D004195:Disease Models, Animal; D044127:Epigenesis, Genetic; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000235:genetics* / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D000076104:Oligodendrocyte Transcription Factor 2; D011379:Prognosis; D011836:Radiation Tolerance / Q000235:genetics*; D015398:Signal Transduction; D059467:Transcriptome; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D018960:Hyaluronan Receptors; D016328:NF-kappa B; D009419:Nerve Tissue Proteins; D000076104:Oligodendrocyte Transcription Factor 2; D014409:Tumor Necrosis Factor-alpha; C405708:OLIG2 protein, human