Glioblastoma hijacks microglial gene expression to support tumor growth

Abstract

Background: Glioblastomas are the most common and lethal primary brain tumors. Microglia, the resident immune cells of the brain, survey their environment and respond to pathogens, toxins, and tumors. Glioblastoma cells communicate with microglia, in part by releasing extracellular vesicles (EVs). Despite the presence of large numbers of microglia in glioblastoma, the tumors continue to grow, and these neuroimmune cells appear incapable of keeping the tumor in check. To understand this process, we analyzed gene expression in microglia interacting with glioblastoma cells. Methods: We used RNASeq of isolated microglia to analyze the expression patterns of genes involved in key microglial functions in mice with glioblastoma. We focused on microglia that had taken up tumor-derived EVs and therefore were within and immediately adjacent to the tumor. Results: We show that these microglia have downregulated expression of genes involved in sensing tumor cells and tumor-derived danger signals, as well as genes used for tumor killing. In contrast, expression of genes involved in facilitating tumor spread was upregulated. These changes appear to be in part EV-mediated, since intracranial injection of EVs in normal mice led to similar transcriptional changes in microglia. We observed a similar microglial transcriptomic signature when we analyzed datasets from human patients with glioblastoma. Conclusion: Our data define a microglia Glioblastoma specific phenotype, whereby glioblastomas have hijacked gene expression in the neuroimmune system to favor avoiding tumor sensing, suppressing the immune response, clearing a path for invasion, and enhancing tumor propagation. For further exploration, we developed an interactive online tool at http://www.glioma-microglia.com with all expression data and additional functional and pathway information for each gene.

Comparative Analysis Identifies Similarities between the Human and Murine Microglial Sensomes

“…Murine and human microglia can also respond in a similar way when confronted with pathological conditions. Recently, we showed that both the mouse and human microglial sensing potential is reduced in the context of glioma [ 3 ]. This suggests that microglia in the context of a tumor have a reduced capability to sense danger and can thus not fully execute their host-versus-tumor response.…”

“…Within a healthy brain, microglia have an important role in brain development and maintenance by clearing (cellular) debris. In pathological conditions, however, microglia can either limit disease progression or they can actually increase the burden of disease [ 2 , 3 , 4 ]. Recently, in addition to homeostatic microglia, a small subtype of microglia has been described based on their gene expression profile and role in disease progression, termed disease associated microglia (DAM) [ 4 , 5 , 6 ].…”

“…These 100 genes include purinergic receptors, cytokine receptors, chemokines, Fc receptors, pattern recognition receptors, extracellular matrix (ECM) receptors, endogenous ligands receptors, sensors, transporters, and proteins involved in cell–cell interactions. The expression of the murine sensome genes decreases during aging and has recently also been reported to be downregulated in the presence of a glioma [ 3 ]. In addition, downregulation of the sensome genes is observed directly after traumatic brain injury (TBI), with expression being restored to baseline over time [ 9 ].…”

“…Here, we have analyzed and discussed a number of microglia bulk and single cell RNAseq datasets from mouse and human disease models and found a number of sensome genes downregulated over time or over the course of disease [ 4 , 10 , 11 , 12 , 13 ]. The decrease in sensome expression could result in accelerated neurodegeneration of the brain or in the case of an existing neoplasm in enhanced tumor progression [ 3 , 7 , 9 ].…”

GlioM&M: Web-based tool for studying circulating and infiltrating monocytes and macrophages in glioma

“…Glioma is a complex disease and the composition of the tumor environment, including glioma-infiltrating monocytes and macrophages, as well as microglia (Maas, Abels et al) has a substantial effect on tumor growth and response to therapy 36 . To elucidate the role of these cells in glioma we have aimed to decipher the molecular profile of these stromal cells.…”