Control of glioblastoma tumorigenesis by feed-forward cytokine signaling.
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.
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.
Arezu
A
Jahani-Asl
Ottawa Hospital Research Institute, Ottawa, Ontario, 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.
Hang
H
Yin
Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada.|Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
Vahab D
VD
Soleimani
Department of Oncology, McGill University, Montreal, Quebec, Canada.|Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada.
Takrima
T
Haque
Department of Cell Biology &Anatomy, University of Calgary, Calgary, Alberta, Canada.
H Artee
HA
Luchman
Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.|Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada.
Natasha C
NC
Chang
Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.|Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada.
Marie-Claude
MC
Sincennes
Department of Neurobiology, Harvard Medical School, Boston, Massachusetts, USA.
Sidharth V
SV
Puram
Olivia Newton-John Cancer Research Institute, School of Cancer Medicine, La Trobe University, Melbourne, Australia.
Andrew M
AM
Scott
Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.|Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada.
Ian A J
IA
Lorimer
Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.|Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada.|Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada.
Theodore J
TJ
Perkins
Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.|Department of Pathology, Harvard Medical School, Boston, Massachusetts, USA.
Keith L
KL
Ligon
Department of Cell Biology &Anatomy, University of Calgary, Calgary, Alberta, Canada.
Samuel
S
Weiss
Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.|Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada.
Michael A
MA
Rudnicki
Department of Neurobiology, Harvard Medical School, Boston, Massachusetts, USA.|Department of Neuroscience, Washington University School of Medicine, St. Louis, Missouri, USA.
Azad
A
Bonni
D000818:Animals; D001932:Brain Neoplasms / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism*; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008297:Male; D008822:Mice, Transgenic; D009368:Neoplasm Transplantation / Q000379:methods; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*
D016207:Cytokines; D050796:STAT3 Transcription Factor; C410723:epidermal growth factor receptor VIII; D066246:ErbB Receptors