@article{9e98fe53a1f6461aa5063728daea1717,
title = "Control of glioblastoma tumorigenesis by feed-forward cytokine signaling",
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.",
author = "Arezu Jahani-As and Hang Yin and Soleimani, {Vahab D.} and Takrima Haque and Luchman, {H. Artee} and Chang, {Natasha C.} and Sincennes, {Marie Claude} and Puram, {Sidharth V.} and Scott, {Andrew M.} and Lorimer, {Ian A.J.} and Perkins, {Theodore J.} and Ligon, {Keith L.} and Samuel Weiss and Rudnicki, {Michael A.} and Azad Bonni",
note = "Funding Information: These studies were carried out with support of grants to A.B. from the US National Institutes for Health (NS064007) and the Mathers Foundation, to M.A.R. from the US National Institutes for Health (R01AR044031), the Canadian Institutes for Health Research (CIHR, MOP-81288), and to A.J.-A. from the new investigator startup funds at the LDI/McGill University. M.A.R. is funded as the Canada Research Chair in Molecular Genetics. V.D.S. is funded as the Canada research chair in stem cell epigenetics. A.J.-A., H.Y. and N.C.C. were supported by postdoctoral fellowships from the CIHR. H.A.L. and S.W. are supported by grants from the Alberta Cancer Foundation and the Stem Cell Network. A.M.S. is supported by National Health and Medical Research Council grant and the Operational Infrastructure Support Program provided by the Victorian Government. We thank C. Porter at the Ottawa Hospital Research Institute for critical help with genomic data analyses. Publisher Copyright: {\textcopyright} 2016 Nature America, Inc. All rights reserved.",
year = "2016",
month = apr,
day = "26",
doi = "10.1038/nn.4295",
language = "English",
volume = "19",
pages = "798--806",
journal = "Nature neuroscience",
issn = "1097-6256",
number = "6",
}