Journal
NATURE NEUROSCIENCE
Volume 19, Issue 6, Pages 798-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nn.4295
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Funding
- US National Institutes for Health [NS064007, R01AR044031]
- Mathers Foundation
- Canadian Institutes for Health Research (CIHR) [MOP-81288]
- new investigator startup funds at the LDI/McGill University
- Canada Research Chair in Molecular Genetics
- Canada research chair in stem cell epigenetics
- CIHR
- Alberta Cancer Foundation
- Stem Cell Network
- National Health and Medical Research Council
- Alberta Innovates [201201230] Funding Source: researchfish
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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.
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