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Mer receptor tyrosine kinase inhibition impedes glioblastoma multiforme migration and alters cellular morphology

Oncogene volume 31, pages 4171–4181 (2012)Cite this article

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Abstract

Glioblastoma multiforme (GBM) is an aggressive brain tumor, fatal within 1 year from diagnosis in most patients despite intensive multimodality therapy. The migratory and microscopically invasive nature of GBM as well as its resistance to chemotherapy renders conventional therapies inadequate in its treatment. Although Mer receptor tyrosine kinase (RTK) inhibition has been shown to decrease the long-term survival and improve the chemosensitivity of GBM in vitro, its role in malignant cellular migration has not been previously evaluated. In this study, we report for the first time a role for Mer RTK in brain tumor migration and show that Mer inhibition profoundly impedes GBM migration and alters cellular morphology. Our data demonstrate that Mer RTK inhibition results in altered signaling through focal adhesion kinase (FAK) and RhoA GTPase and a transformation of cytoskeletal organization, suggesting both molecular and structural mechanisms for the abrogation of migration. We also describe a novel and translational method of Mer RTK inhibition using a newly developed monoclonal antibody, providing proof of principle for future evaluation of Mer-targeted translational therapies in the treatment of GBM. Previous findings implicating Mer signaling in glioblastoma survival and chemotherapy resistance coupled with our discovery of the role of Mer RTK in GBM cellular migration support the development of novel Mer-targeted therapies for this devastating disease.

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Acknowledgements

We thank Rachel Linger, PhD for her expertise and insight into this project. We thank Jennifer Schlegel for production of the Mer add-back vector, the Advanced Light Microscopy Core Facility at the University of Colorado School of Medicine for their technical support in microscopy, and the University of Colorado Cancer Center Tissue Culture Core for their technical support in monoclonal antibody development. DKG is supported by NIH R01 1CA137078. AKK is generously supported by the St Baldrick's Foundation and the NIH K12 HD068372Child Health Research Career Development Award.

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Authors and Affiliations

  1. Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, USA

    A E J Rogers, J P Le, S Sather, B M Pernu, D K Graham, A M Pierce & A K Keating

  2. Department of Pediatrics, Children's Hospital Colorado, Aurora, CO, USA

    A E J Rogers, D K Graham & A K Keating

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  1. A E J Rogers
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  2. J P Le
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Correspondence to A K Keating.

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Rogers, A., Le, J., Sather, S. et al. Mer receptor tyrosine kinase inhibition impedes glioblastoma multiforme migration and alters cellular morphology. Oncogene 31, 4171–4181 (2012). https://doi.org/10.1038/onc.2011.588

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