EGFRvIII mutations can emerge as late and heterogenous events in glioblastoma development and promote angiogenesis through Src activation

Eskil Eskilsson, Gro V. Rosland, Krishna M. Talasila, Stian Knappskog, Olivier Keunen, Andrea Sottoriva, Sarah Foerster, Gergely Solecki, Torfinn Taxt, Radovan Jirik, Sabrina Fritah, Patrick N. Harter, Kristjan Välk, Jubayer Al Hossain, Justin V. Joseph, Roza Jahedi, Halala S. Saed, Sara G. Piccirillo, Inma Spiteri, Philipp Euskirchen & 10 others Grazia Graziani, Thomas Daubon, Morten Lund-Johansen, Per Øyvind Enger, Frank Winkler, Christoph A. Ritter, Simone P. Niclou, Colin Watts, Rolf Bjerkvig, Hrvoje Miletic

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

Background. Amplification of the epidermal growth factor receptor (EGFR) and its mutant EGFRvIII are among the most common genetic alterations in glioblastoma (GBM), the most frequent and most aggressive primary brain tumor. Methods. In the present work, we analyzed the clonal evolution of these major EGFR aberrations in a small cohort of GBM patients using a unique surgical multisampling technique. Furthermore, we overexpressed both receptors separately and together in 2 patient-derived GBM stem cell lines (GSCs) to analyze their functions in vivo in orthotopic xenograft models. Results. In human GBM biopsies, we identified EGFR amplification as an early event because EGFRvIII mutations emerge from intratumoral heterogeneity later in tumor development. To investigate the biological relevance of this distinct developmental pattern, we established experimental model systems. In these models, EGFR+ tumor cells showed activation of classical downstream signaling pathways upon EGF stimulation and displayed enhanced invasive growth without evidence of angiogenesis in vivo. In contrast, EGFRvIII+ tumors were driven by activation of the prototypical Src family kinase c-Src that promoted VEGF secretion leading to angiogenic tumor growth. Conclusions. The presented work shows that sequential EGFR amplification and EGFRvIII mutations might represent concerted evolutionary events that drive the aggressive nature of GBM by promoting invasion and angiogenesis via distinct signaling pathways. In particular, c-SRC may be an attractive therapeutic target for tumors harboring EGFRvIII as we identified this protein specifically mediating angiogenic tumor growth downstream of EGFRvIII.

Original languageEnglish (US)
Pages (from-to)1-12
Number of pages12
JournalNeuro-Oncology
Volume18
Issue number12
DOIs
StatePublished - Jan 1 2016

Fingerprint

Glioblastoma
Epidermal Growth Factor Receptor
Mutation
Neoplasms
Growth
Clonal Evolution
src-Family Kinases
Epidermal Growth Factor
Heterografts
Brain Neoplasms
Vascular Endothelial Growth Factor A
epidermal growth factor receptor VIII
Theoretical Models
Stem Cells
Biopsy
Cell Line
Proteins

Keywords

  • Angiogenesis
  • EGFR
  • EGFRvIII
  • Glioblastoma
  • Invasion

ASJC Scopus subject areas

  • Oncology
  • Clinical Neurology
  • Cancer Research

Cite this

Eskilsson, E., Rosland, G. V., Talasila, K. M., Knappskog, S., Keunen, O., Sottoriva, A., ... Miletic, H. (2016). EGFRvIII mutations can emerge as late and heterogenous events in glioblastoma development and promote angiogenesis through Src activation. Neuro-Oncology, 18(12), 1-12. https://doi.org/10.1093/neuonc/now113

EGFRvIII mutations can emerge as late and heterogenous events in glioblastoma development and promote angiogenesis through Src activation. / Eskilsson, Eskil; Rosland, Gro V.; Talasila, Krishna M.; Knappskog, Stian; Keunen, Olivier; Sottoriva, Andrea; Foerster, Sarah; Solecki, Gergely; Taxt, Torfinn; Jirik, Radovan; Fritah, Sabrina; Harter, Patrick N.; Välk, Kristjan; Al Hossain, Jubayer; Joseph, Justin V.; Jahedi, Roza; Saed, Halala S.; Piccirillo, Sara G.; Spiteri, Inma; Euskirchen, Philipp; Graziani, Grazia; Daubon, Thomas; Lund-Johansen, Morten; Enger, Per Øyvind; Winkler, Frank; Ritter, Christoph A.; Niclou, Simone P.; Watts, Colin; Bjerkvig, Rolf; Miletic, Hrvoje.

In: Neuro-Oncology, Vol. 18, No. 12, 01.01.2016, p. 1-12.

Research output: Contribution to journalArticle

Eskilsson, E, Rosland, GV, Talasila, KM, Knappskog, S, Keunen, O, Sottoriva, A, Foerster, S, Solecki, G, Taxt, T, Jirik, R, Fritah, S, Harter, PN, Välk, K, Al Hossain, J, Joseph, JV, Jahedi, R, Saed, HS, Piccirillo, SG, Spiteri, I, Euskirchen, P, Graziani, G, Daubon, T, Lund-Johansen, M, Enger, PØ, Winkler, F, Ritter, CA, Niclou, SP, Watts, C, Bjerkvig, R & Miletic, H 2016, 'EGFRvIII mutations can emerge as late and heterogenous events in glioblastoma development and promote angiogenesis through Src activation', Neuro-Oncology, vol. 18, no. 12, pp. 1-12. https://doi.org/10.1093/neuonc/now113
Eskilsson, Eskil ; Rosland, Gro V. ; Talasila, Krishna M. ; Knappskog, Stian ; Keunen, Olivier ; Sottoriva, Andrea ; Foerster, Sarah ; Solecki, Gergely ; Taxt, Torfinn ; Jirik, Radovan ; Fritah, Sabrina ; Harter, Patrick N. ; Välk, Kristjan ; Al Hossain, Jubayer ; Joseph, Justin V. ; Jahedi, Roza ; Saed, Halala S. ; Piccirillo, Sara G. ; Spiteri, Inma ; Euskirchen, Philipp ; Graziani, Grazia ; Daubon, Thomas ; Lund-Johansen, Morten ; Enger, Per Øyvind ; Winkler, Frank ; Ritter, Christoph A. ; Niclou, Simone P. ; Watts, Colin ; Bjerkvig, Rolf ; Miletic, Hrvoje. / EGFRvIII mutations can emerge as late and heterogenous events in glioblastoma development and promote angiogenesis through Src activation. In: Neuro-Oncology. 2016 ; Vol. 18, No. 12. pp. 1-12.
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abstract = "Background. Amplification of the epidermal growth factor receptor (EGFR) and its mutant EGFRvIII are among the most common genetic alterations in glioblastoma (GBM), the most frequent and most aggressive primary brain tumor. Methods. In the present work, we analyzed the clonal evolution of these major EGFR aberrations in a small cohort of GBM patients using a unique surgical multisampling technique. Furthermore, we overexpressed both receptors separately and together in 2 patient-derived GBM stem cell lines (GSCs) to analyze their functions in vivo in orthotopic xenograft models. Results. In human GBM biopsies, we identified EGFR amplification as an early event because EGFRvIII mutations emerge from intratumoral heterogeneity later in tumor development. To investigate the biological relevance of this distinct developmental pattern, we established experimental model systems. In these models, EGFR+ tumor cells showed activation of classical downstream signaling pathways upon EGF stimulation and displayed enhanced invasive growth without evidence of angiogenesis in vivo. In contrast, EGFRvIII+ tumors were driven by activation of the prototypical Src family kinase c-Src that promoted VEGF secretion leading to angiogenic tumor growth. Conclusions. The presented work shows that sequential EGFR amplification and EGFRvIII mutations might represent concerted evolutionary events that drive the aggressive nature of GBM by promoting invasion and angiogenesis via distinct signaling pathways. In particular, c-SRC may be an attractive therapeutic target for tumors harboring EGFRvIII as we identified this protein specifically mediating angiogenic tumor growth downstream of EGFRvIII.",
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AU - Eskilsson, Eskil

AU - Rosland, Gro V.

AU - Talasila, Krishna M.

AU - Knappskog, Stian

AU - Keunen, Olivier

AU - Sottoriva, Andrea

AU - Foerster, Sarah

AU - Solecki, Gergely

AU - Taxt, Torfinn

AU - Jirik, Radovan

AU - Fritah, Sabrina

AU - Harter, Patrick N.

AU - Välk, Kristjan

AU - Al Hossain, Jubayer

AU - Joseph, Justin V.

AU - Jahedi, Roza

AU - Saed, Halala S.

AU - Piccirillo, Sara G.

AU - Spiteri, Inma

AU - Euskirchen, Philipp

AU - Graziani, Grazia

AU - Daubon, Thomas

AU - Lund-Johansen, Morten

AU - Enger, Per Øyvind

AU - Winkler, Frank

AU - Ritter, Christoph A.

AU - Niclou, Simone P.

AU - Watts, Colin

AU - Bjerkvig, Rolf

AU - Miletic, Hrvoje

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N2 - Background. Amplification of the epidermal growth factor receptor (EGFR) and its mutant EGFRvIII are among the most common genetic alterations in glioblastoma (GBM), the most frequent and most aggressive primary brain tumor. Methods. In the present work, we analyzed the clonal evolution of these major EGFR aberrations in a small cohort of GBM patients using a unique surgical multisampling technique. Furthermore, we overexpressed both receptors separately and together in 2 patient-derived GBM stem cell lines (GSCs) to analyze their functions in vivo in orthotopic xenograft models. Results. In human GBM biopsies, we identified EGFR amplification as an early event because EGFRvIII mutations emerge from intratumoral heterogeneity later in tumor development. To investigate the biological relevance of this distinct developmental pattern, we established experimental model systems. In these models, EGFR+ tumor cells showed activation of classical downstream signaling pathways upon EGF stimulation and displayed enhanced invasive growth without evidence of angiogenesis in vivo. In contrast, EGFRvIII+ tumors were driven by activation of the prototypical Src family kinase c-Src that promoted VEGF secretion leading to angiogenic tumor growth. Conclusions. The presented work shows that sequential EGFR amplification and EGFRvIII mutations might represent concerted evolutionary events that drive the aggressive nature of GBM by promoting invasion and angiogenesis via distinct signaling pathways. In particular, c-SRC may be an attractive therapeutic target for tumors harboring EGFRvIII as we identified this protein specifically mediating angiogenic tumor growth downstream of EGFRvIII.

AB - Background. Amplification of the epidermal growth factor receptor (EGFR) and its mutant EGFRvIII are among the most common genetic alterations in glioblastoma (GBM), the most frequent and most aggressive primary brain tumor. Methods. In the present work, we analyzed the clonal evolution of these major EGFR aberrations in a small cohort of GBM patients using a unique surgical multisampling technique. Furthermore, we overexpressed both receptors separately and together in 2 patient-derived GBM stem cell lines (GSCs) to analyze their functions in vivo in orthotopic xenograft models. Results. In human GBM biopsies, we identified EGFR amplification as an early event because EGFRvIII mutations emerge from intratumoral heterogeneity later in tumor development. To investigate the biological relevance of this distinct developmental pattern, we established experimental model systems. In these models, EGFR+ tumor cells showed activation of classical downstream signaling pathways upon EGF stimulation and displayed enhanced invasive growth without evidence of angiogenesis in vivo. In contrast, EGFRvIII+ tumors were driven by activation of the prototypical Src family kinase c-Src that promoted VEGF secretion leading to angiogenic tumor growth. Conclusions. The presented work shows that sequential EGFR amplification and EGFRvIII mutations might represent concerted evolutionary events that drive the aggressive nature of GBM by promoting invasion and angiogenesis via distinct signaling pathways. In particular, c-SRC may be an attractive therapeutic target for tumors harboring EGFRvIII as we identified this protein specifically mediating angiogenic tumor growth downstream of EGFRvIII.

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KW - Invasion

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