Control of glioblastoma tumorigenesis by feed-forward cytokine signaling

Arezu Jahani-As, Hang Yin, Vahab D. Soleimani, Takrima Haque, H. Artee Luchman, Natasha C. Chang, Marie Claude Sincennes, Sidharth V. Puram, Andrew M. Scott, Ian A.J. Lorimer, Theodore J. Perkins, Keith L. Ligon, Samuel Weiss, Michael A. Rudnicki, Azad Bonni

Research output: Contribution to journalArticlepeer-review

48 Scopus citations

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.

Original languageEnglish
Pages (from-to)798-806
Number of pages9
JournalNature neuroscience
Volume19
Issue number6
DOIs
StatePublished - Apr 26 2016

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