STEM-09. WNT16 MEDIATES MESENCHYMAL TRANSITION AND RESISTANCE IN GLIOBLASTOMA

Abstract Glioblastoma (GBM) is highly resistant to standard chemo-radiation therapy. GBM resistance and recurrence is mainly driven by glioblastoma stem-like cells (GSCs) that display enhanced DNA repair and phenotypic plasticity under therapeutic stress. Specifically, the transition of GSC from a proneural (PN) to a mesenchymal (MES) state is considered a hallmark of therapeutic resistance. To investigate mechanisms underlying therapy induced PN-to-MES transition, we conducted bulk RNA-sequencing of patient-derived PN- and MES-GSC lines treated with ionizing radiation (IR). We identified WNT16, a member of the wingless-type MMTV integration site family of secreted ligands, as significantly upregulated in irradiated PN-GSCs. Culturing GSC with recombinant WNT16 significantly induced MES-marker expression, and conversely shRNA-mediated knockdown of WNT16 reduced MES-transition. WNT16 and IR activate canonical β-catenin signaling in GSC to induce MES-transition and IR-resistance. Blocking β-catenin signaling with the brain penetrant BC2059 reduced MES marker expression and enhanced DNA damage sensitizing GSC to IR. BC2059 also sensitized GBM tumors to IR, reduced tumor growth and improved animal survival in both syngeneic and orthotopic xenograft mouse models. Collectively, our findings highlight a key role for WNT16 in mediating therapy-induced GSC plasticity and resistance.