title: Identification of an EGFRvIII-JNK2-HGF/c-Met-Signaling Axis Required for Intercellular Crosstalk and Glioblastoma Multiforme Cell Invasion.
abstract: Glioblastoma multiforme (GBM) is the most aggressive and common form of adult brain cancer. Current therapeutic strategies include surgical resection, followed by radiotherapy and chemotherapy. Despite such aggressive multimodal therapy, prognosis remains poor, with a median patient survival of 14 months. A proper understanding of the molecular drivers responsible for GBM progression are therefore necessary to instruct the development of novel targeted agents and enable the design of effective treatment strategies. Activation of the c-Jun N-terminal kinase isoform 2 (JNK2) is reported in primary brain cancers, where it associates with the histologic grade and amplification of the epidermal growth factor receptor (EGFR). In this manuscript, we demonstrate an important role for JNK2 in the tumor promoting an invasive capacity of EGFR variant III, a constitutively active mutant form of the receptor commonly found in GBM. Expression of EGFR variant III induces transactivation of JNK2 in GBM cells, which is required for a tumorigenic phenotype in vivo. Furthermore, JNK2 expression and activity is required to promote increased cellular invasion through stimulation of a hepatocyte growth factor-c-Met signaling circuit, whereby secretion of this extracellular ligand activates the receptor tyrosine kinase in both a cell autonomous and nonautonomous manner. Collectively, these findings demonstrate the cooperative and parallel activation of multiple RTKs in GBM and suggest that the development of selective JNK2 inhibitors could be therapeutically beneficial either as single agents or in combination with inhibitors of EGFR and/or c-Met.
authors.affiliation: Department of Molecular Therapeutics (V.C.S., M.L., I.A., V.Q., D.F., Y.L., D.R.D.), Informatics Core, Scripps Research Institute, Jupiter, Florida (M.F.) and Cancer Research Technology Discovery Laboratories, Jonas Webb Building, Babraham Research Campus, Cambridge, United Kingdom (L.H.R.).
authors.forename: Vanessa C
authors.initials: VC
authors.lastname: Saunders
authors.affiliation: Department of Molecular Therapeutics (V.C.S., M.L., I.A., V.Q., D.F., Y.L., D.R.D.), Informatics Core, Scripps Research Institute, Jupiter, Florida (M.F.) and Cancer Research Technology Discovery Laboratories, Jonas Webb Building, Babraham Research Campus, Cambridge, United Kingdom (L.H.R.).
authors.forename: Marie
authors.initials: M
authors.lastname: Lafitte
authors.affiliation: Department of Molecular Therapeutics (V.C.S., M.L., I.A., V.Q., D.F., Y.L., D.R.D.), Informatics Core, Scripps Research Institute, Jupiter, Florida (M.F.) and Cancer Research Technology Discovery Laboratories, Jonas Webb Building, Babraham Research Campus, Cambridge, United Kingdom (L.H.R.).
authors.forename: Isabel
authors.initials: I
authors.lastname: Adrados
authors.affiliation: Department of Molecular Therapeutics (V.C.S., M.L., I.A., V.Q., D.F., Y.L., D.R.D.), Informatics Core, Scripps Research Institute, Jupiter, Florida (M.F.) and Cancer Research Technology Discovery Laboratories, Jonas Webb Building, Babraham Research Campus, Cambridge, United Kingdom (L.H.R.).
authors.forename: Victor
authors.initials: V
authors.lastname: Quereda
authors.affiliation: Department of Molecular Therapeutics (V.C.S., M.L., I.A., V.Q., D.F., Y.L., D.R.D.), Informatics Core, Scripps Research Institute, Jupiter, Florida (M.F.) and Cancer Research Technology Discovery Laboratories, Jonas Webb Building, Babraham Research Campus, Cambridge, United Kingdom (L.H.R.).
authors.forename: Daniel
authors.initials: D
authors.lastname: Feurstein
authors.affiliation: Department of Molecular Therapeutics (V.C.S., M.L., I.A., V.Q., D.F., Y.L., D.R.D.), Informatics Core, Scripps Research Institute, Jupiter, Florida (M.F.) and Cancer Research Technology Discovery Laboratories, Jonas Webb Building, Babraham Research Campus, Cambridge, United Kingdom (L.H.R.).
authors.forename: YuanYuan
authors.initials: Y
authors.lastname: Ling
authors.affiliation: Department of Molecular Therapeutics (V.C.S., M.L., I.A., V.Q., D.F., Y.L., D.R.D.), Informatics Core, Scripps Research Institute, Jupiter, Florida (M.F.) and Cancer Research Technology Discovery Laboratories, Jonas Webb Building, Babraham Research Campus, Cambridge, United Kingdom (L.H.R.).
authors.forename: Mohammad
authors.initials: M
authors.lastname: Fallahi
authors.affiliation: Department of Molecular Therapeutics (V.C.S., M.L., I.A., V.Q., D.F., Y.L., D.R.D.), Informatics Core, Scripps Research Institute, Jupiter, Florida (M.F.) and Cancer Research Technology Discovery Laboratories, Jonas Webb Building, Babraham Research Campus, Cambridge, United Kingdom (L.H.R.).
authors.forename: Laura H
authors.initials: LH
authors.lastname: Rosenberg
authors.affiliation: Department of Molecular Therapeutics (V.C.S., M.L., I.A., V.Q., D.F., Y.L., D.R.D.), Informatics Core, Scripps Research Institute, Jupiter, Florida (M.F.) and Cancer Research Technology Discovery Laboratories, Jonas Webb Building, Babraham Research Campus, Cambridge, United Kingdom (L.H.R.) ducketdr@scripps.edu.
authors.forename: Derek R
authors.initials: DR
authors.lastname: Duckett
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000096:biosynthesis*; D005909:Glioblastoma / Q000378:metabolism* / Q000473:pathology; D017228:Hepatocyte Growth Factor / Q000096:biosynthesis*; D006801:Humans; D007365:Intercellular Junctions / Q000378:metabolism; D008297:Male; D051379:Mice; D008819:Mice, Nude; D048056:Mitogen-Activated Protein Kinase 9 / Q000096:biosynthesis*; D009361:Neoplasm Invasiveness / Q000473:pathology; D020794:Receptor Protein-Tyrosine Kinases / Q000096:biosynthesis*; D015398:Signal Transduction / Q000502:physiology*; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: C066855:HGF protein, human; C410723:epidermal growth factor receptor VIII; D017228:Hepatocyte Growth Factor; D048056:Mitogen-Activated Protein Kinase 9; D066246:ErbB Receptors; C080835:RON protein; D020794:Receptor Protein-Tyrosine Kinases