Wnt/β-catenin signaling is a key downstream mediator of MET signaling in glioblastoma stem cells

Abstract

Glioblastoma (GBM) is the most lethal and common type of primary brain tumor. Recent evidence suggests that a subpopulation of GBMcells (glioblastoma stem cells [GSCs]) is critical for tumor progression, invasion, and therapeutic resistance.We and others have demonstrated thatMET, a receptor tyrosine kinase, positively regulates the stemness phenotype and radioresistance of GSCs. Here, we interrogated the downstream effector pathways of MET signaling in GSCs. Methods. We have established a series of GSCs and xenograft tumors derived from freshly dissociated specimens from patients with GBMand characterized a subpopulation enriched with MET activation (METhigh/+). Through global expression profiling and subsequent pathways analysis, we identified signaling pathways that are enriched in METhigh/+ populations, one of which is Wnt/β-catenin signaling pathway. To determine molecular interaction and the biological consequences of MET and Wnt/β-catenin signaling, we used pharmacological and shRNA-mediated genetic inhibition and performed various molecular and cellular analyses, including flow cytometry, immunohistochemistry, and clonogenicity assays. Results. We found thatWnt/β-catenin signaling is highly active in METhigh/+ cells, compared with bulk tumor cells.We also showed thatWnt/β-catenin signaling activities in GBM are directly modulated by the addition of ligand-mediated MET activation or MET inhibition. Furthermore, the ectopic expression of active-β-catenin (S37A and S45Y) rescued the phenotypic effects caused by MET inhibition. Conclusion. These data suggest that Wnt/β-catenin signaling is a key downstream effector of MET signaling and contributes to the maintenance of GSC and GBM malignancy.© The Author(s) 2012.