EXPLORING WNT REGULATION IN GLIOMA-PROPAGATING CELLS, AND WNT INHIBITION AS A THERAPEUTIC STRATEGY

Abstract

Brain tumors such as gliomas have poor prognosis despite advanced surgical intervention and adjuvant chemo- and radiotherapies. The highly infiltrative and recurrent nature of this disease has often been attributed to stem-like cells with extensive self-renewal potential. These cells, termed ¿glioma-propagating cells¿ (GPCs), can be isolated from clinical material, and we now have a way to cryopreserve them, with maintenance of essential primary tumor hallmarks such as karyotype and transcriptomic profile. Our foundational work established that histologically similar glioblastoma (GBM, grade IV) tumors yield GPCs with very distinct transcriptomic profiles, suggesting molecular heterogeneity and possibly accounting for the frequently observed inter-patient variability to treatment response. Importantly, we were able to show in the major glioma variants, oligodendroglial tumors and GBM, that GPCs contain signaling pathways, manifested as transcriptomic programs which dictate primary tumor behavior, disease progression and patient survival outcome. These findings emphasize that GPCs are clinically relevant and can serve as a valuable cellular platform for further studies. We explored one of these transcriptomic programs, Wnt, in detail. We showed pharmacologically and genetically that Wnt activation promotes GPC growth and tumorigenicity, mediated through the MITF transcription factor. GPCs (oligodendroglial and GBM) with high MITF expression were more sensitive to pathway inhibition, highlighting the limitation of relying solely on histology to diagnose and subsequently treat patients. Our study provides evidence that tumor growth can be mitigated by targeting Wnt signaling.