PubMed | Stemgen Spa., ISBReMIT Institute for Stem Cell Biology, Bioinformatic Unit, University of Milan Bicocca and 6 more.
Type: | Journal: Cancer research | Year: 2016
Brain invasion by glioblastoma (hGBM) determines prognosis, recurrence and lethality in patients, but no master factor coordinating the invasive properties of GBM has been identified. Here we report evidence favouring such a role for the non-canonical WNT family member Wnt5a. We found the most invasive gliomas to be characterized by Wnt5a overexpression, which correlated with poor prognosis and also discriminated infiltrating mesenchymal GBM from poorly motile proneural and classical GBM. Indeed, Wnt5a overexpression associated with tumor-promoting stem-like characteristics (TPC) in defining the character of highly-infiltrating mesenchymal GBM cells (Wnt5aHigh). Inhibiting Wnt5a in mesenchymal GBM TPC suppressed their infiltrating capability. Conversely, enforcing high levels of Wnt5a activated an infiltrative, mesenchymal-like program in classical GBM TPC and Wnt5aLow mesenchymal TPC. In intracranial mouse xenograft models of GBM, inhibiting Wnt5a activity blocked brain invasion and increased host survival. Overall, our results highlight Wnt5a as a master regulator of brain invasion, specifically TPC, and they provide a therapeutic rationale to target it in GBM patients.