PO-473 WNT6 expression in glioblastoma: mechanistic, functional and clinical implications

Introduction Glioblastoma (GBM) is a universally fatal brain cancer, for which novel therapies targeting specific underlying oncogenic events are urgently needed. While the Wnt pathway has been shown to be frequently activated in GBM, constituting a potential therapeutic target, the relevance of WNT6, an activator of this pathway, remains unknown. Material and methods WNT6 protein and mRNA levels were evaluated in GBM. WNT6 expression was silenced or overexpressed in GBM cells to assess functional effects in vitro and in vivo . Phospho-kinase arrays were used to identify WNT6-signalling pathways, and significant associations with stem-cell features and cancer-related pathways were validated in patients. Survival analyses were performed with Cox regression and Log-rank tests. Results and discussions We show that WNT6 is significantly overexpressed in GBMs, as compared to lower-grade gliomas and normal brain, at mRNA and protein levels. Functionally, WNT6 increases typical oncogenic activities in GBM cells, including viability, proliferation, glioma stem-cell capacity, invasion, migration, and resistance to temozolomide chemotherapy. Concordantly, in in vivo orthotopic GBM mice models, WNT6 associates with shorter overall survival and increased features of tumour aggressiveness, in both overexpressing and silencing models. Mechanistically, WNT6 contributes to activate typical oncogenic pathways, including Src and STAT, which intertwined with the WNT pathway may be critical effectors of WNT6-associated aggressiveness in GBM. Clinically, we establish WNT6 as an independent prognostic biomarker of shorter survival in GBM patients from several independent cohorts. Conclusion This work defines new functional and mechanistic roles of WNT6 in GBM, establishing its clinical value as a novel prognostic biomarker. Our findings also support the inhibition of WNT6 as an attractive therapeutic option for this deadly disease, and support the molecular prognostic stratification of patients, which may aid the clinicians in rational treatment decisions.