Abstract 3777: The role of IFITMs in maintaining glioma stem cells

Glioblastoma (GBM), one of the most lethal and heterogeneous primary brain tumors, contains cellular hierarchies with both quiescent and self-renewing highly tumorigenic glioblastoma stem cells (GSCs). Cancer stem cells within the context of the brain likely contribute to a lack of progress in patient survival time as they appear to have an innate resistance to both chemotherapeutic drugs and radiotherapy. The aim of this study is to elucidate how constitutive expression of interferons (IFNs) and their downstream signalling pathways maintain GSCs thereby supporting treatment resistance and tumor reoccurrence. To understand the mechanism of action of a subset of IFN regulated genes, originally characterized as a signature for radiation and chemotherapy resistance (IRDS), a panel of patient derived glioma stem cells was generated and manipulated using CRISPR/Cas9 mediated gene-editing. Phenotypic changes in growth, viability and drug resistance were characterised in the edited cells and linked to molecular level events using transcriptomic and proteomic techniques. Using this approach, in conjunction with patient tissue analysis, signalling under basal as well as IFN-activated conditions was studied in the context of GSC status. Immunohistopathology of a glioma tissue micro-array identified an increased expression of IFN induced transmembrane receptors (IFITMs), which co-localised with Nestin, around the blood vessels suggesting that IFITM positive cells were in the stem cell niche. Further analysis showed the presence of both IFITM1 and IFITM3 in GSCs and established that loss of IFITM function impacted on growth rate and cell cycle progression as well as treatment sensitivity. By using wild-type and gene-edited GSC to focus on the relationship between IFITM1 and IFITM3, we have compelling phenotypic and molecular evidence that IFN-induced changes in the localisation of IFITMs impact on the ability of stem cells to ‘escape9 normal growth control mechanisms. Taking into consideration the constitutive expression of interferons in the tumor microenvironment, our study provides evidence that IFITMs regulate glioma stem cell self-renewal and are involved in maintaining a quiescent population which can escape chemotherapy. Citation Format: Erisa Nita, Bernard Evers, Marta Nekulova, Gillian Morrison, Kathryn Ball. The role of IFITMs in maintaining glioma stem cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3777.