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Activated EGFR signaling increases proliferation, survival, and migration and blocks neuronal differentiation in post-natal neural stem cells

  • Laboratory Investigation - Human/Animal Tissue
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Abstract

Recent evidence supports the notion that transformation of undifferentiated neural stem cell (NSC) precursors may contribute to the development of glioblastoma multiforme (GBM). The over-expression and mutation of the epidermal growth factor receptor (EGFR), along with other cellular pathway mutations, plays a significant role in GBM maintenance progression. Though EGFR signaling is important in determining neural cell fate and conferring astrocyte differentiation, there is a limited understanding of its role in NSC and tumor stem cell (TSC) biology. We hypothesized that EGFR expression and mutation in post-natal NSCs may contribute to cellular aggressiveness including enhanced cellular proliferation, survival and migration. Stable subclones of C17.2 murine NSCs were transfected to over-express either the wild-type EGFR (wtEGFR) or its most common mutated variant EGFRvIII. Activated EGFR signaling in these cells induced behaviors characteristic of GBM TSCs, including enhanced proliferation, survival and migration, even in the absence of EGF ligand. wtEGFR activation was also found to block neuronal differentiation and was associated with a dramatic increase in chemotaxis in the presence of EGF. EGFRvIII expression lead to an increase in NSC proliferation and survival, while it simultaneously blocked neuronal differentiation and promoted glial fate. Our findings suggest that activated EGFR signaling enhances the aggressiveness of NSCs. Understanding the regulatory mechanisms of NSCs may lend insight into deregulated mechanisms of GBM TSC invasion, proliferation, survival and resistance to current treatment modalities.

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Acknowledgements

We are especially grateful to Dr. Glickstein, Dr. Musatov, Dr. Falcon, and Dr. Heck for their technical advice and FACS core facility at CIPF. Angel Ayuso-Sacido is a recipient of a Postdoctoral Fellowships from Fulbright/MEC program, RETIC, Ministerio de Educacion y Ciencia, Spain. This work was supported in part by grants from The American Brain Tumor Association (JAB), the American Association of Neurological Surgeons (JAB), the Starr Foundation Stem Cell Award (JAB) and K08 CA130985-01A1 (JAB) from the NIH/NCI.

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Authors and Affiliations

  1. Neurosurgical Laboratory for Translational Stem Cell Research, Department of Neurosurgery, Weill Cornell Brain Tumor Center, Weill Cornell Medical College of Cornell University, New York, NY, USA

    Angel Ayuso-Sacido, Jennifer A. Moliterno, Sebila Kratovac & John A. Boockvar

  2. Department of Neurology and Neuroscience, Weill Cornell Medical College of Cornell University, New York, NY, USA

    Neeta S. Roy

  3. Department of Neurological Surgery, University of Pennsylvania School of Medicine, Philadelphia, PA, USA

    Gurpreet S. Kapoor & Donald M. O’Rourke

  4. Department of Neurological Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

    Eric C. Holland

  5. Department of Cell Morphology, Centro de Investigación Principe Felipe and RETICS-CIBERNED, AVDA Autopista del Saler 16, 46012, Valencia, Spain

    Angel Ayuso-Sacido & Jose Manuel García-Verdugo

  6. Department of Neurological Surgery, Weill Cornell Medical College of Cornell University, 510 E 70th Street, New York, NY, 10021, USA

    John A. Boockvar

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  1. Angel Ayuso-Sacido
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Correspondence to Angel Ayuso-Sacido or John A. Boockvar.

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Ayuso-Sacido, A., Moliterno, J.A., Kratovac, S. et al. Activated EGFR signaling increases proliferation, survival, and migration and blocks neuronal differentiation in post-natal neural stem cells. J Neurooncol 97, 323–337 (2010). https://doi.org/10.1007/s11060-009-0035-x

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