The TNF receptor family member Fn14 is highly expressed in recurrent glioblastoma and in GBM patient-derived xenografts with acquired temozolomide resistance

David S. Hersh, Bryan G. Harder, Alison Roos, Sen Peng, Jonathan E. Heath, Teklu Legesse, Anthony J. Kim, Graeme F. Woodworth, Nhan Tran, Jeffrey A. Winkles

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Background. Glioblastoma (GBM) is a difficult to treat brain cancer that nearly uniformly recurs, and recurrent tumors are largely therapy resistant. Our prior work has demonstrated an important role for the tumor necrosis factor-like weak inducer of apoptosis (TWEAK) receptor fibroblast growth factor-inducible 14 (Fn14) in GBM pathobiology. In this study, we investigated Fn14 expression in recurrent GBM and in the setting of temozolomide (TMZ) resistance. Methods. Fn14 mRNA expression levels in nonneoplastic brain, primary (newly diagnosed) GBM, and recurrent GBM (post-chemotherapy and radiation) specimens were obtained from The Cancer Genome Atlas data portal. Immunohistochemistry was performed using nonneoplastic brain, patient-matched primary and recurrent GBM, and gliosarcoma (GSM) specimens to examine Fn14 protein levels. Western blot analysis was used to compare Fn14 expression in parentalTMZ-sensitive or matchedTMZ-resistant patient-derived xenografts (PDXs) established from primary or recurrent tumor samples.The migratory capacity of control and Fn14-depletedTMZ-resistant GBM cells was assessed using the transwell migration assay. Results. We found that Fn14 is more highly expressed in recurrent GBM tumors than their matched primary GBM counterparts. Fn14 expression is also significantly elevated in GSM tumors. GBM PDX cells with acquiredTMZ resistance have higher Fn14 levels and greater migratory capacity than their corresponding parentalTMZ-sensitive cells, and the migratory difference is due, at least in part, to Fn14 expression in theTMZ-resistant cells. Conclusions. This study demonstrates that the Fn14 gene is highly expressed in recurrent GBM, GSM, andTMZ-resistant GBM PDX tumors.These findings suggest that Fn14 may be a valuable therapeutic target or drug delivery portal for treatment of recurrent GBM and GSM patients.

Original languageEnglish (US)
Pages (from-to)1321-1330
Number of pages10
JournalNeuro-Oncology
Volume20
Issue number10
DOIs
StatePublished - Jan 1 2018

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temozolomide
Tumor Necrosis Factor Receptors
Glioblastoma
Heterografts
Gliosarcoma
Neoplasms

Keywords

  • Fn14
  • Glioblastoma
  • Gliosarcoma
  • Migration
  • Temozolomide

ASJC Scopus subject areas

  • Oncology
  • Clinical Neurology
  • Cancer Research

Cite this

The TNF receptor family member Fn14 is highly expressed in recurrent glioblastoma and in GBM patient-derived xenografts with acquired temozolomide resistance. / Hersh, David S.; Harder, Bryan G.; Roos, Alison; Peng, Sen; Heath, Jonathan E.; Legesse, Teklu; Kim, Anthony J.; Woodworth, Graeme F.; Tran, Nhan; Winkles, Jeffrey A.

In: Neuro-Oncology, Vol. 20, No. 10, 01.01.2018, p. 1321-1330.

Research output: Contribution to journalArticle

Hersh, DS, Harder, BG, Roos, A, Peng, S, Heath, JE, Legesse, T, Kim, AJ, Woodworth, GF, Tran, N & Winkles, JA 2018, 'The TNF receptor family member Fn14 is highly expressed in recurrent glioblastoma and in GBM patient-derived xenografts with acquired temozolomide resistance', Neuro-Oncology, vol. 20, no. 10, pp. 1321-1330. https://doi.org/10.1093/neuonc/noy063
Hersh, David S. ; Harder, Bryan G. ; Roos, Alison ; Peng, Sen ; Heath, Jonathan E. ; Legesse, Teklu ; Kim, Anthony J. ; Woodworth, Graeme F. ; Tran, Nhan ; Winkles, Jeffrey A. / The TNF receptor family member Fn14 is highly expressed in recurrent glioblastoma and in GBM patient-derived xenografts with acquired temozolomide resistance. In: Neuro-Oncology. 2018 ; Vol. 20, No. 10. pp. 1321-1330.
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abstract = "Background. Glioblastoma (GBM) is a difficult to treat brain cancer that nearly uniformly recurs, and recurrent tumors are largely therapy resistant. Our prior work has demonstrated an important role for the tumor necrosis factor-like weak inducer of apoptosis (TWEAK) receptor fibroblast growth factor-inducible 14 (Fn14) in GBM pathobiology. In this study, we investigated Fn14 expression in recurrent GBM and in the setting of temozolomide (TMZ) resistance. Methods. Fn14 mRNA expression levels in nonneoplastic brain, primary (newly diagnosed) GBM, and recurrent GBM (post-chemotherapy and radiation) specimens were obtained from The Cancer Genome Atlas data portal. Immunohistochemistry was performed using nonneoplastic brain, patient-matched primary and recurrent GBM, and gliosarcoma (GSM) specimens to examine Fn14 protein levels. Western blot analysis was used to compare Fn14 expression in parentalTMZ-sensitive or matchedTMZ-resistant patient-derived xenografts (PDXs) established from primary or recurrent tumor samples.The migratory capacity of control and Fn14-depletedTMZ-resistant GBM cells was assessed using the transwell migration assay. Results. We found that Fn14 is more highly expressed in recurrent GBM tumors than their matched primary GBM counterparts. Fn14 expression is also significantly elevated in GSM tumors. GBM PDX cells with acquiredTMZ resistance have higher Fn14 levels and greater migratory capacity than their corresponding parentalTMZ-sensitive cells, and the migratory difference is due, at least in part, to Fn14 expression in theTMZ-resistant cells. Conclusions. This study demonstrates that the Fn14 gene is highly expressed in recurrent GBM, GSM, andTMZ-resistant GBM PDX tumors.These findings suggest that Fn14 may be a valuable therapeutic target or drug delivery portal for treatment of recurrent GBM and GSM patients.",
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T1 - The TNF receptor family member Fn14 is highly expressed in recurrent glioblastoma and in GBM patient-derived xenografts with acquired temozolomide resistance

AU - Hersh, David S.

AU - Harder, Bryan G.

AU - Roos, Alison

AU - Peng, Sen

AU - Heath, Jonathan E.

AU - Legesse, Teklu

AU - Kim, Anthony J.

AU - Woodworth, Graeme F.

AU - Tran, Nhan

AU - Winkles, Jeffrey A.

PY - 2018/1/1

Y1 - 2018/1/1

N2 - Background. Glioblastoma (GBM) is a difficult to treat brain cancer that nearly uniformly recurs, and recurrent tumors are largely therapy resistant. Our prior work has demonstrated an important role for the tumor necrosis factor-like weak inducer of apoptosis (TWEAK) receptor fibroblast growth factor-inducible 14 (Fn14) in GBM pathobiology. In this study, we investigated Fn14 expression in recurrent GBM and in the setting of temozolomide (TMZ) resistance. Methods. Fn14 mRNA expression levels in nonneoplastic brain, primary (newly diagnosed) GBM, and recurrent GBM (post-chemotherapy and radiation) specimens were obtained from The Cancer Genome Atlas data portal. Immunohistochemistry was performed using nonneoplastic brain, patient-matched primary and recurrent GBM, and gliosarcoma (GSM) specimens to examine Fn14 protein levels. Western blot analysis was used to compare Fn14 expression in parentalTMZ-sensitive or matchedTMZ-resistant patient-derived xenografts (PDXs) established from primary or recurrent tumor samples.The migratory capacity of control and Fn14-depletedTMZ-resistant GBM cells was assessed using the transwell migration assay. Results. We found that Fn14 is more highly expressed in recurrent GBM tumors than their matched primary GBM counterparts. Fn14 expression is also significantly elevated in GSM tumors. GBM PDX cells with acquiredTMZ resistance have higher Fn14 levels and greater migratory capacity than their corresponding parentalTMZ-sensitive cells, and the migratory difference is due, at least in part, to Fn14 expression in theTMZ-resistant cells. Conclusions. This study demonstrates that the Fn14 gene is highly expressed in recurrent GBM, GSM, andTMZ-resistant GBM PDX tumors.These findings suggest that Fn14 may be a valuable therapeutic target or drug delivery portal for treatment of recurrent GBM and GSM patients.

AB - Background. Glioblastoma (GBM) is a difficult to treat brain cancer that nearly uniformly recurs, and recurrent tumors are largely therapy resistant. Our prior work has demonstrated an important role for the tumor necrosis factor-like weak inducer of apoptosis (TWEAK) receptor fibroblast growth factor-inducible 14 (Fn14) in GBM pathobiology. In this study, we investigated Fn14 expression in recurrent GBM and in the setting of temozolomide (TMZ) resistance. Methods. Fn14 mRNA expression levels in nonneoplastic brain, primary (newly diagnosed) GBM, and recurrent GBM (post-chemotherapy and radiation) specimens were obtained from The Cancer Genome Atlas data portal. Immunohistochemistry was performed using nonneoplastic brain, patient-matched primary and recurrent GBM, and gliosarcoma (GSM) specimens to examine Fn14 protein levels. Western blot analysis was used to compare Fn14 expression in parentalTMZ-sensitive or matchedTMZ-resistant patient-derived xenografts (PDXs) established from primary or recurrent tumor samples.The migratory capacity of control and Fn14-depletedTMZ-resistant GBM cells was assessed using the transwell migration assay. Results. We found that Fn14 is more highly expressed in recurrent GBM tumors than their matched primary GBM counterparts. Fn14 expression is also significantly elevated in GSM tumors. GBM PDX cells with acquiredTMZ resistance have higher Fn14 levels and greater migratory capacity than their corresponding parentalTMZ-sensitive cells, and the migratory difference is due, at least in part, to Fn14 expression in theTMZ-resistant cells. Conclusions. This study demonstrates that the Fn14 gene is highly expressed in recurrent GBM, GSM, andTMZ-resistant GBM PDX tumors.These findings suggest that Fn14 may be a valuable therapeutic target or drug delivery portal for treatment of recurrent GBM and GSM patients.

KW - Fn14

KW - Glioblastoma

KW - Gliosarcoma

KW - Migration

KW - Temozolomide

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