Activated astrocytes drive the accumulation of apolipoprotein E at the brain tumor edge.

While tumor-associated macrophages (TAMs) have been extensively studied, the role of tumor-associated astrocytes (TAAs) in glioma progression is less explored. Astrocytes are crucial in maintaining lipid homeostasis by synthesizing cholesterol and apolipoprotein E (APOE) in the brain. However, the contribution of astrocytes in supporting the metabolic needs of tumor cells within the tumor microenvironment (TME) is still poorly understood. This study aims to investigate how astrocytes contribute to the unique brain TME by examining the spatial distribution of APOE and its correlation with glial cells. This study examined the spatial distribution of APOE in gliomas with two murine brain tumor models: ALTS1C1 and GL261. To validate astrocyte APOE secretion, in situ hybridization (ISH) for APOE mRNA and immunofluorescence (IF) staining for GFAP were performed. Immunofluorescence (IF) staining showed that APOE was accumulated at the tumor edge. ISH analysis confirmed that activated astrocytes were the primary cells responsible for the increased APOE in this region. Flow cytometry and IF staining demonstrated that TAMs were also associated with increased APOE expression in the tumor core. This study provides the first evidence that astrocytes at the tumor edge are activated and upregulated for APOE secretion. These brain tumor edge-associated astrocytes are responsible for the accumulation of APOE in this region and create a unique metabolic environment, which may contribute to brain tumor invasion and resistance to therapy.