CSIG-06EGFRvIII REQUIRES OSMR AS A CO-RECEPTOR TO DRIVE GLIOBLASTOMA PATHOGENESIS

EGFRvIII/STAT3 signaling plays a significant role in glioblastoma pathogenesis. Here, we identify the cytokine receptor OSMR as a direct target gene of the transcription factor STAT3 in mouse astrocytes and human brain tumor stem cells (BTSCs). Strikingly, OSMR forms a receptor complex with EGFRvIII in human BTSCs and mouse astrocytes. Accordingly, gene expression analyses reveal that EGFRvIII, STAT3, and OSMR share a common network of target genes. Interestingly, in astrocytes that do not express EGFRvIII, the ligand OSM stimulates the interaction of OSMR with wild type EGFR, phosphorylation of EGFR, and STAT3 activation. Importantly, knockdown of OSMR strongly suppresses cell proliferation and in vivo tumor growth of EGFRvIII-expressing murine glioblastoma cells and human BTSC xenografts. Our findings define OSMR as a critical regulator of glioblastoma tumor growth that orchestrates a feed forward signaling mechanism with EGFRvIII and STAT3 to drive glioblastoma tumorigenesis.