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Schaefer, Thorsten; Ramadoss, Archana; Leu, Severina; Tintignac, Lionel; Tostado, Cristobal; Bink, Andrea; Schürch, Christoph; Müller, Joëlle; Schärer, Jonas; Moffa, Giusi; Demougin, Philippe; Moes, Suzette; Stippich, Christoph; Falbo, Simona; Neddersen, Heike; Bucher, Heiner; Frank, Stephan; Jenö, Paul; Lengerke, Claudia; Ritz, Marie‐Françoise; Mariani, Luigi; Boulay, Jean‐Louis

Regulation of glioma cell invasion by 3q26 gene products PIK3CA, SOX2 and OPA1

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  • Medientyp: E-Artikel
  • Titel: Regulation of glioma cell invasion by 3q26 gene products PIK3CA, SOX2 and OPA1
  • Beteiligte: Schaefer, Thorsten; Ramadoss, Archana; Leu, Severina; Tintignac, Lionel; Tostado, Cristobal; Bink, Andrea; Schürch, Christoph; Müller, Joëlle; Schärer, Jonas; Moffa, Giusi; Demougin, Philippe; Moes, Suzette; Stippich, Christoph; Falbo, Simona; Neddersen, Heike; Bucher, Heiner; Frank, Stephan; Jenö, Paul; Lengerke, Claudia; Ritz, Marie‐Françoise; Mariani, Luigi; Boulay, Jean‐Louis
  • Erschienen: Wiley, 2019
  • Erschienen in: Brain Pathology
  • Sprache: Englisch
  • DOI: 10.1111/bpa.12670
  • ISSN: 1015-6305; 1750-3639
  • Schlagwörter: Neurology (clinical) ; Pathology and Forensic Medicine ; General Neuroscience
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  • Beschreibung: <jats:title>Abstract</jats:title><jats:p>Diffuse gliomas progress by invading neighboring brain tissue to promote postoperative relapse. Transcription factor <jats:italic>SOX2 </jats:italic>is highly expressed in invasive gliomas and maps to chromosome region 3q26 together with the genes for PI3K/AKT signaling activator PIK3CA and effector molecules of mitochondria fusion and cell invasion, MFN1 and OPA1. Gene copy number analysis at 3q26 from 129 glioma patient biopsies revealed mutually exclusive <jats:italic>SOX2</jats:italic> amplifications (26%) and <jats:italic>OPA1</jats:italic> losses (19%). Both forced <jats:italic>SOX2</jats:italic> expression and <jats:italic>OPA1</jats:italic> inactivation increased LN319 glioma cell invasion <jats:italic>in vitro</jats:italic> and promoted cell dispersion <jats:italic>in vivo</jats:italic> in xenotransplanted <jats:italic>D. rerio</jats:italic> embryos. While PI3 kinase activity sustained SOX2 expression, pharmacological PI3K/AKT pathway inhibition decreased invasion and resulted in SOX2 nucleus‐to‐cytoplasm translocation in an mTORC1‐independent manner. Chromatin immunoprecipitation and luciferase reporter gene assays together demonstrated that SOX2 <jats:italic>trans‐</jats:italic>activates <jats:italic>PIK3CA</jats:italic> and <jats:italic>OPA1</jats:italic>. Thus, SOX2 activates PI3K/AKT signaling in a positive feedback loop, while <jats:italic>OPA1 </jats:italic>deletion is interpreted to counteract <jats:italic>OPA1 trans</jats:italic>‐activation. Remarkably, neuroimaging of human gliomas with high <jats:italic>SOX2</jats:italic> or low <jats:italic>OPA1</jats:italic> genomic imbalances revealed significantly larger necrotic tumor zone volumes, corresponding to higher invasive capacities of tumors, while autologous necrotic cells are capable of inducing higher invasion in <jats:italic>SOX2 </jats:italic>overexpressing or <jats:italic>OPA1 </jats:italic>knocked‐down relative to parental LN319. We thus propose necrosis volume as a surrogate marker for the assessment of glioma invasive potential. Whereas glioma invasion is activated by a PI3K/AKT‐SOX2 loop, it is reduced by a cryptic invasion suppressor SOX2‐OPA1 pathway. Thus, PI3K/AKT‐SOX2 and mitochondria fission represent connected signaling networks regulating glioma invasion.</jats:p>
  • Zugangsstatus: Freier Zugang