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EphB2 receptor controls proliferation/migration dichotomy of glioblastoma by interacting with focal adhesion kinase

Oncogene volume 31, pages 5132–5143 (2012)Cite this article

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Abstract

Glioblastoma multiforme (GBM) is the most frequent and aggressive primary brain tumors in adults. Uncontrolled proliferation and abnormal cell migration are two prominent spatially and temporally disassociated characteristics of GBMs. In this study, we investigated the role of the receptor tyrosine kinase EphB2 in controlling the proliferation/migration dichotomy of GBM. We studied EphB2 gain of function and loss of function in glioblastoma-derived stem-like neurospheres, whose in vivo growth pattern closely replicates human GBM. EphB2 expression stimulated GBM neurosphere cell migration and invasion, and inhibited neurosphere cell proliferation in vitro. In parallel, EphB2 silencing increased tumor cell proliferation and decreased tumor cell migration. EphB2 was found to increase tumor cell invasion in vivo using an internally controlled dual-fluorescent xenograft model. Xenografts derived from EphB2-overexpressing GBM neurospheres also showed decreased cellular proliferation. The non-receptor tyrosine kinase focal adhesion kinase (FAK) was found to be co-associated with and highly activated by EphB2 expression, and FAK activation facilitated focal adhesion formation, cytoskeleton structure change and cell migration in EphB2-expressing GBM neurosphere cells. Taken together, our findings indicate that EphB2 has pro-invasive and anti-proliferative actions in GBM stem-like neurospheres mediated, in part, by interactions between EphB2 receptors and FAK. These novel findings suggest that tumor cell invasion can be therapeutically targeted by inhibiting EphB2 signaling, and that optimal antitumor responses to EphB2 targeting may require concurrent use of anti-proliferative agents.

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Acknowledgements

This work was supported by the Maryland Stem Cell Research Fund (MSCRFE) 2009-0126-00 (SX), NIH NS43987 (JL) and the James S McDonnell Foundation (JL). We thank Dr Hugo Guerrero-Cázares for technical advice and Miss Mir Shanaz Hossain for technical assistance. We also thank Mr Hao Zhang from Johns Hopkins School of Public Health for assistance with flow cytometric analysis.

Author contributions: SDW: Collection and assembly of data, data analysis and interpretation, final approval; PR, BL, J-PR, YL, CRG: Collection and assembly of data, final approval; JL: Financial support, administrative support, data analysis and interpretation, manuscript writing, final approval. SX: Conception and design, financial support, administrative support, collection and assembly of data, data analysis and interpretation, manuscript writing, final approval.

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Authors and Affiliations

  1. Hugo W Moser Research Institute at Kennedy Krieger, Baltimore, MD, USA

    S D Wang, P Rath, B Lal, J-P Richard, Y Li, J Laterra & S Xia

  2. Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA

    P Rath, B Lal, J-P Richard, Y Li, J Laterra & S Xia

  3. Department of Neurosurgery, Johns Hopkins School of Medicine, Baltimore, MD, USA

    C R Goodwin

  4. Department of Oncology, Johns Hopkins School of Medicine, Baltimore, MD, USA

    J Laterra

  5. Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore, MD, USA

    J Laterra

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  1. S D Wang
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Wang, S., Rath, P., Lal, B. et al. EphB2 receptor controls proliferation/migration dichotomy of glioblastoma by interacting with focal adhesion kinase. Oncogene 31, 5132–5143 (2012). https://doi.org/10.1038/onc.2012.16

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