Glioma Cells Achieve Malignant Progression by Fusion with Macrophages to Gain High SLC7A5 Expression

Abstract Background Glioma is the most prevalent primary tumor of the central nervous system (CNS) in adults, and its high proliferative and invasive capacities are typically associated with a poor prognosis. Cell fusions are a crucial phenomenon in both physiological and pathological processes. Within tumors, tumor cells can acquire diverse gene expression profiles and undergo malignant progression through fusion events with themselves or other somatic cells. This process leads to the emergence of stem cell characteristics, drug resistance properties, immune evasion abilities, and enhanced migration and invasion capacities. Macrophages (MФs) represent the predominant cell type within glioma immune microenvironments and are important partners for fusion events with glioma cells. However, the biological characteristics and underlying mechanisms of MФ-glioma fusion hybrids remain incompletely elucidated. Results We validated the presence of MФ-glioma double positive cells through analysis of glioma single-cell RNA sequencing (scRNA-seq) data and examination of glioma specimens. We successfully established the MФ-glioma cell fusion hybrid models in vitro. Subsequent propidium iodide (PI) staining combined with flow cytometry analysis revealed a significant increase in the chromosome content of hybrid cells. Research on the biological characteristics of MФ-glioma fusion hybrids has revealed their heightened proliferation and invasion capabilities. Further mechanistic investigations have elucidated that SLC7A5, a tumor-associated gene originating from parental MФs, orchestrates the augmented proliferative and invasive capabilities of hybrid cells via activation of the mTOR-RPS6 signaling pathway. Furthermore, the MФ-glioma fusion hybrids exhibited heightened sensitivity to a specific inhibitor of SLC7A5 (JPH203) compared to their parental cells. Conclusion Glioma cells achieve malignant progression by acquiring high expression of the tumor-associated gene SLC7A5 through fusion with MФs. This discovery provides a new perspective on the malignant biology of gliomas.