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Title: | Control of glioblastoma tumorigenesis by feed-forward cytokine signaling | Austin Authors: | Jahani-Asl, Arezu;Yin, Hang;Soleimani, Vahab D;Haque, Takrima;Luchman, H Artee;Chang, Natasha C;Sincennes, Marie-Claude;Puram, Sidharth V;Scott, Andrew M ;Lorimer, Ian A J;Perkins, Theodore J;Ligon, Keith L;Weiss, Samuel;Rudnicki, Michael A;Bonni, Azad | Affiliation: | Department of Neurobiology, Harvard Medical School, Boston, Massachusetts, USA Department of Neuroscience, Washington University School of Medicine, St. Louis, Missouri, USA Ottawa Hospital Research Institute, Ottawa, Ontario, Canada Department of Oncology, McGill University, Montreal, Quebec, Canada Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada Department of Biochemistry, University of Georgia, Athens, Georgia, USA Molecular Biology Centre for Molecular Medicine, University of Georgia, Athens, Georgia, USA Department of Human Genetics, McGill University, Montreal, Quebec, Canada Department of Cell Biology &Anatomy, University of Calgary, Calgary, Alberta, Canada Olivia Newton-John Cancer Research Institute, School of Cancer Medicine, La Trobe University, Melbourne, Australia Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA Department of Pathology, Harvard Medical School, Boston, Massachusetts, USA |
Issue Date: | Jun-2016 | Date: | 2016-04-25 | Publication information: | Nature Neuroscience 2016; 19(6): 798-806 | Abstract: | EGFRvIII-STAT3 signaling is important in glioblastoma pathogenesis. Here, we identified the cytokine receptor OSMR as a direct target gene of the transcription factor STAT3 in mouse astrocytes and human brain tumor stem cells (BTSCs). We found that OSMR functioned as an essential co-receptor for EGFRvIII. OSMR formed a physical complex with EGFRvIII, and depletion of OSMR impaired EGFRvIII-STAT3 signaling. Conversely, pharmacological inhibition of EGFRvIII phosphorylation inhibited the EGFRvIII-OSMR interaction and activation of STAT3. EGFRvIII-OSMR signaling in tumors operated constitutively, whereas EGFR-OSMR signaling in nontumor cells was synergistically activated by the ligands EGF and OSM. Finally, knockdown of OSMR strongly suppressed cell proliferation and tumor growth of mouse glioblastoma cells and human BTSC xenografts in mice, and prolonged the lifespan of these mice. Our findings identify OSMR as a critical regulator of glioblastoma tumor growth that orchestrates a feed-forward signaling mechanism with EGFRvIII and STAT3 to drive tumorigenesis. | URI: | https://ahro.austin.org.au/austinjspui/handle/1/16773 | DOI: | 10.1038/nn.4295 | ORCID: | 0000-0002-6656-295X | Journal: | Nature Neuroscience | PubMed URL: | https://pubmed.ncbi.nlm.nih.gov/27110918 | Type: | Journal Article | Subjects: | Brain Neoplasms Cell Transformation, Neoplastic Cytokines Glioblastoma Signal Transduction |
Appears in Collections: | Journal articles |
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