ANGI-04. HOST INTERFERON SIGNALING MODULATES EPITHELIAL-TO-MESENCHYMAL TRANSITION IN GLIOBLASTOMA INVASION THROUGH BRAIN CD73

Abstract Glioblastoma (GBM) is an aggressive malignant brain tumor that invades adjacent normal brain tissue. The underlying mechanisms driving GBM invasion remain poorly understood. Unlike other solid tumors, GBM is infiltrated by various normal brain cells, including neurons, oligodendrocytes, oligodendrocyte progenitor cells (OPCs), microglia, and astrocytes. Recent studies suggest that brain cells infiltrating GBM may promote tumor growth and invasion. In this study, we observed that mouse GBM tumor GSC005 grown in immunodeficient (RAG1-KO, NSG) mice exhibited a more invasive phenotype compared to those in immunocompetent C57BL/6J mice. Immunofluorescence staining revealed the presence of vimentin+ and GFAP+ cells at the tumor-border interface, forming capsule-like structures around small tumor islands. Bulk mRNA-seq analysis showed that GSC005 tumors in NSG mice displayed an upregulated mesenchymal signature, characterized by epithelial-to-mesenchymal transition (EMT), and downregulation of type-I and type-II interferon signaling. Our data further suggests that host-intrinsic and therapeutic type-I interferon promotes, while type-II interferon inhibits, the GBM mesenchymal signature. CD73, a key regulator of the EMT process, was found to be upregulated in GSC005 tumors in NSG mice compared to C57BL/6J mice. Mechanistic studies revealed that type-I interferon increases CD73 expression in both tumor and stromal cells, such as tumor-associated astrocytes (mAS), while type-II interferon suppresses CD73 in mAS. Functional assays indicated that CD73 modulates both type-I and type-II interferon signaling-mediated GBM invasion. These findings suggest that therapies inducing type-I or type-II interferon signaling in GBM may reciprocally regulate CD73-mediated mesenchymal transitions, impacting GBM invasion.