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 Joshi; Christopher 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

doi:10.1016/j.ccr.2013.08.001

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

Department of Pathology

Research output: Contribution to journal › Article › peer-review

729 Citations (Scopus)

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 language	English
Pages (from-to)	331-346
Number of pages	16
Journal	Cancer Cell
Volume	24
Issue number	3
DOIs	https://doi.org/10.1016/j.ccr.2013.08.001
Publication status	Published - 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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.ccr.2013.08.001

Cite this

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

@article{41ef502cd543490db06e35ce6be1b9d9,

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 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.",

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

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{\textquoteright} 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. ",

year = "2013",

month = sep,

day = "9",

doi = "10.1016/j.ccr.2013.08.001",

language = "English",

volume = "24",

pages = "331--346",

journal = "Cancer Cell",

issn = "1535-6108",

publisher = "Cell Press",

number = "3",

}

Bhat, KPL, Balasubramaniyan, V, Vaillant, B, Ezhilarasan, R, Hummelink, K, Hollingsworth, F, Wani, K, Heathcock, L, James, JD, Goodman, LD, Conroy, S, Long, L, Lelic, N, Wang, S, Gumin, J, Raj, D, Kodama, Y, Raghunathan, A, Olar, A, Joshi, K, Pelloski, CE, Heimberger, A, Kim, SH, Cahill, DP, Rao, G, DenDunnen, WFA, Boddeke, HWGM, Phillips, HS, Nakano, I, Lang, FF, Colman, H, Sulman, EP & Aldape, K 2013, 'Mesenchymal Differentiation Mediated by NF-κB Promotes Radiation Resistance in Glioblastoma', Cancer Cell, vol. 24, no. 3, pp. 331-346. https://doi.org/10.1016/j.ccr.2013.08.001

TY - JOUR

T1 - Mesenchymal Differentiation Mediated by NF-κB Promotes Radiation Resistance in Glioblastoma

AU - Bhat, Krishna P.L.

AU - Balasubramaniyan, Veerakumar

AU - Vaillant, Brian

AU - Ezhilarasan, Ravesanker

AU - Hummelink, Karlijn

AU - Hollingsworth, Faith

AU - Wani, Khalida

AU - Heathcock, Lindsey

AU - James, Johanna D.

AU - Goodman, Lindsey D.

AU - Conroy, Siobhan

AU - Long, Lihong

AU - Lelic, Nina

AU - Wang, Suzhen

AU - Gumin, Joy

AU - Raj, Divya

AU - Kodama, Yoshinori

AU - Raghunathan, Aditya

AU - Olar, Adriana

AU - Joshi, Kaushal

AU - Pelloski, Christopher E.

AU - Heimberger, Amy

AU - Kim, Se Hoon

AU - Cahill, Daniel P.

AU - Rao, Ganesh

AU - DenDunnen, Wilfred F.A.

AU - Boddeke, Hendrikus W.G.M.

AU - Phillips, Heidi S.

AU - Nakano, Ichiro

AU - Lang, Frederick F.

AU - Colman, Howard

AU - Sulman, Erik P.

AU - Aldape, Kenneth

N1 - 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.

PY - 2013/9/9

Y1 - 2013/9/9

N2 - 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.

AB - 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.

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UR - http://www.scopus.com/inward/citedby.url?scp=84883656941&partnerID=8YFLogxK

U2 - 10.1016/j.ccr.2013.08.001

DO - 10.1016/j.ccr.2013.08.001

M3 - Article

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AN - SCOPUS:84883656941

SN - 1535-6108

VL - 24

SP - 331

EP - 346

JO - Cancer Cell

JF - Cancer Cell

IS - 3

ER -

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

Abstract

Bibliographical note

All Science Journal Classification (ASJC) codes

UN SDGs

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