title: Mer receptor tyrosine kinase inhibition impedes glioblastoma multiforme migration and alters cellular morphology.
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.
authors.affiliation: Department of Pediatrics, University of Colorado School of Medicine, and Department of Pediatrics, Children's Hospital Colorado, Aurora, CO 80045, USA.
authors.forename: A E J
authors.initials: AE
authors.lastname: Rogers
authors.forename: J P
authors.initials: JP
authors.lastname: Le
authors.forename: S
authors.initials: S
authors.lastname: Sather
authors.forename: B M
authors.initials: BM
authors.lastname: Pernu
authors.forename: D K
authors.initials: DK
authors.lastname: Graham
authors.forename: A M
authors.initials: AM
authors.lastname: Pierce
authors.forename: A K
authors.initials: AK
authors.lastname: Keating
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics*; D004789:Enzyme Activation / Q000235:genetics; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism; D015870:Gene Expression; D005909:Glioblastoma / Q000235:genetics* / Q000473:pathology*; D006801:Humans; D051379:Mice; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000276:immunology; D034622:RNA Interference; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000276:immunology; D015398:Signal Transduction; D000076202:c-Mer Tyrosine Kinase; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D011518:Proto-Oncogene Proteins; C097072:MERTK protein, human; D020794:Receptor Protein-Tyrosine Kinases; D000076202:c-Mer Tyrosine Kinase; D051416:Focal Adhesion Protein-Tyrosine Kinases; D020742:rhoA GTP-Binding Protein