Abstract
BACKGROUND: Glioblastoma (GBM) is an aggressive malignant brain-tumor that invades adjacent normal brain tissue. Unlike other solid tumors, GBM is infiltrated by various normal brain cells. METHODS: We analyzed tumor invasion in the murine GSC005 glioma model using both immunodeficient and immunocompetent mice, focusing on the role of host-intrinsic and therapeutic interferon signaling in regulating glioblastoma (GBM) invasion. RESULTS: 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. 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. CONCLUSION: 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.