Wirthschaft, Peter and Bode, Julia and Soni, Himanshu and Dietrich, Fabio and Kruewel, Thomas and Fischer, Bernd and Knobbe-Thomsen, Christiane B. and Rossetti, Giulia and Hentschel, Andreas and Mack, Norman and Schoenig, Kai and Breckwoldt, Michael O. and Schmandke, Andre and Pusch, Stefan and Medenbach, Jan and Bendszus, Martin and Schwab, Martin E. and von Deimling, Andreas and Kool, Marcel and Herold-Mende, Christel and Reifenberger, Guido and Ahrends, Robert and Tews, Bjoern (2019) RhoA regulates translation of the Nogo-A decoy SPARC in white matter-invading glioblastomas. ACTA NEUROPATHOLOGICA, 138 (2). pp. 275-293. ISSN 0001-6322, 1432-0533
Full text not available from this repository. (Request a copy)Abstract
Glioblastomas strongly invade the brain by infiltrating into the white matter along myelinated nerve fiber tracts even though the myelin protein Nogo-A prevents cell migration by activating inhibitory RhoA signaling. The mechanisms behind this long-known phenomenon remained elusive so far, precluding a targeted therapeutic intervention. This study demonstrates that the prevalent activation of AKT in gliomas increases the ER protein-folding capacity and enables tumor cells to utilize a side effect of RhoA activation: the perturbation of the IRE1 alpha-mediated decay of SPARC mRNA. Once translation is initiated, glioblastoma cells rapidly secrete SPARC to block Nogo-A from inhibiting migration via RhoA. By advanced ultramicroscopy for studying single-cell invasion in whole, undissected mouse brains, we show that gliomas require SPARC for invading into white matter structures. SPARC depletion reduces tumor dissemination that significantly prolongs survival and improves response to cytostatic therapy. Our finding of a novel RhoA-IRE1 axis provides a druggable target for interfering with SPARC production and underscores its therapeutic value.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | PROTEIN-COUPLED RECEPTORS; GLIOMA GROWTH; PATHWAY; CANCER; CELLS; MIGRATION; MYELIN; TUMORS; PTEN; GLYCOLYSIS; SPARC; Nogo-A; RhoA; IRE1 alpha; AKT; ENTPD5; Glioblastoma; Invasion; Post-transcriptional regulation; White matter |
| Subjects: | 500 Science > 570 Life sciences |
| Divisions: | Biology, Preclinical Medicine > Institut für Biochemie, Genetik und Mikrobiologie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 02 Apr 2020 05:56 |
| Last Modified: | 02 Apr 2020 05:56 |
| URI: | https://pred.uni-regensburg.de/id/eprint/26545 |
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