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SHP2 regulates proliferation and tumorigenicity of glioma stem cells

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Abstract

SHP2 is a cytoplasmic protein tyrosine phosphatase (PTPase) involved in multiple signaling pathways and was the first identified proto-oncogene PTPase. Previous work in glioblastoma (GBM) has demonstrated the role of SHP2 PTPase activity in modulating the oncogenic phenotype of adherent GBM cell lines. Mutations in PTPN11, the gene encoding SHP2, have been identified with increasing frequency in GBM. Given the importance of SHP2 in developing neural stem cells, and the importance of glioma stem cells (GSCs) in GBM oncogenesis, we explored the functional role of SHP2 in GSCs. Using paired differentiated and stem cell primary cultures, we investigated the association of SHP2 expression with the tumor stem cell compartment. Proliferation and soft agar assays were used to demonstrate the functional contribution of SHP2 to cell growth and transformation. SHP2 expression correlated with SOX2 expression in GSC lines and was decreased in differentiated cells. Forced differentiation of GSCs by removal of growth factors, as confirmed by loss of SOX2 expression, also resulted in decreased SHP2 expression. Lentiviral-mediated knockdown of SHP2 inhibited proliferation. Finally, growth in soft-agar was similarly inhibited by loss of SHP2 expression. Our results show that SHP2 function is required for cell growth and transformation of the GSC compartment in GBM.

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Funding

M.B.-A. is supported by the Novartis Research Foundation, the European Research Council (ERC starting Grant 243211-PTPsBDC), the Swiss Cancer League, the Swiss National Foundation, and the Krebsliga Beider Basel. N.D. is supported by NIH Grant R01-NS-093120. D.M.O. is supported by NIH Grant 5R01NS042645-13. Z.A.B. is supported by the Templeton Family Initative In Neuro-Oncology.

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Author notes

  1. Laura Roccograndi and Zev A. Binder have contributed equally to the work.

Authors and Affiliations

  1. Department of Neurosurgery, University of Pennsylvania School of Medicine, 502 Stemmler Hall, 36th and Hamilton Walk, Philadelphia, PA, 19104, USA

    Laura Roccograndi, Zev A. Binder, Logan Zhang, Nadia Dahmane & Donald M. O’Rourke

  2. Department of Biomedicine, Cancer Metastasis, University of Basel, 4058, Basel, Switzerland

    Nicola Aceto

  3. Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, AL, USA

    Zhuo Zhang

  4. Friedrich Miescher Institute for Biomedical Research, 4058, Basel, Switzerland

    Mohamed Bentires-Alj

  5. Department of Neurosurgery, Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA

    Ichiro Nakano

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  1. Laura Roccograndi
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Correspondence to Donald M. O’Rourke.

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This article does not contain any studies with animals performed by any of the authors. All procedures performed in studies involving human participants were in accordance with the ethical standards of the University of Pennsylvania and with the 1964 Helsinki declaration and its later amendments. The research was conducted in accordance with a Hospital of the University of Pennsylvania’s Institutional Review Board-approved protocol #816686. Written consent was obtained from all patients in accordance with the protocol.

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Roccograndi, L., Binder, Z.A., Zhang, L. et al. SHP2 regulates proliferation and tumorigenicity of glioma stem cells. J Neurooncol 135, 487–496 (2017). https://doi.org/10.1007/s11060-017-2610-x

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