Astrocyte immunometabolic regulation of the tumour microenvironment drives glioblastoma pathogenicity

Abstract

Malignant brain tumours are the cause of a disproportionate level of morbidity and mortality among cancer patients, an unfortunate statistic that has remained constant for decades. Despite considerable advances in the molecular characterization of these tumours, targeting the cancer cells has yet to produce significant advances in treatment. An alternative strategy is to target cells in the glioblastoma microenvironment, such as tumour-associated astrocytes. Astrocytes control multiple processes in health and disease, ranging from maintaining the brain’s metabolic homeostasis, to modulating neuroinflammation. However, their role in glioblastoma pathogenicity is not well understood. Here we report that depletion of reactive astrocytes regresses glioblastoma and prolongs mouse survival. Analysis of the tumour-associated astrocyte translatome revealed astrocytes initiate transcriptional programmes that shape the immune and metabolic compartments in the glioma microenvironment. Specifically, their expression of CCL2 and CSF1 governs the recruitment of tumour-associated macrophages and promotes a pro-tumourigenic macrophage phenotype. Concomitantly, we demonstrate that astrocyte-derived cholesterol is key to glioma cell survival, and that targeting astrocytic cholesterol efflux, via ABCA1, halts tumour progression. In summary, astrocytes control glioblastoma pathogenicity by reprogramming the immunological properties of the tumour microenvironment and supporting the non-oncogenic metabolic dependency of glioblastoma on cholesterol. These findings suggest that targeting astrocyte immunometabolic signalling may be useful in treating this uniformly lethal brain tumour.

NAD + metabolism drives astrocyte proinflammatory reprogramming in central nervous system autoimmunity

“…After this time, the astrocyte monolayer was separated using mild trypsinization (mild T/E) ( 77 ), and the resultant single-cell suspension of astrocytes was plated on poly-L-lysine (0.01 mg/mL; Sigma-Aldrich, #P6282)-coated plates. Primary astrocyte cultures were found to be >99% GFAP + positive by immunofluorescent staining or >99% GLAST + by Fluorescence-activated cell sorting (FACS) staining, with less than 1% microglial cells (IBA-1 + or CD11b + cells, respectively), as previously shown ( 12 ) undefined. Primary human astrocytes (ScienceCell, #1800) were grown according to the manufacturer’s instructions.…”

“…These include participating in the maintenance of the blood–brain barrier (BBB), storing and distributing energetic substrates to neurons and supporting the development of neural cells and synaptogenesis ( 7 – 9 ). Astrocytes respond to acute or chronic stimulation with reactive changes that influence the outcome of a variety of neurological disorders, including MS ( 1 , 10 – 12 ). Accordingly, astrocytes can influence neurotoxicity, modulate the microglial phenotype, regulate the recruitment of inflammatory cells into the CNS, and shape the immunometabolic landscape ( 2 , 3 , 11 – 14 ).…”

“…Astrocytes respond to acute or chronic stimulation with reactive changes that influence the outcome of a variety of neurological disorders, including MS ( 1 , 10 – 12 ). Accordingly, astrocytes can influence neurotoxicity, modulate the microglial phenotype, regulate the recruitment of inflammatory cells into the CNS, and shape the immunometabolic landscape ( 2 , 3 , 11 – 14 ). These activities are driven by transcriptional reprogramming and metabolic adaptations whose contextual diversity and regulation are poorly understood.…”

Mechanism of action of paclitaxel for treating glioblastoma based on single-cell RNA sequencing data and network pharmacology

“…Replication, mismatch repair, and S. aureus infection pathway were activated. GABAergic synapse, insulin secretion, morphine addiction, nicotine addiction, and synaptic vesicle cycle pathways were significantly inhibited, suggesting that immune function was overactivated in the tumor tissues ( Perelroizen et al, 2022 ).…”

Impact of epigenetic reprogramming on antitumor immune responses in glioma

“…The release of lactic acid and the resulting hypoxia lead to the induction of an immunosuppressive TME by mechanisms that include increased secretion of TGF-β, inhibition of the monocyte differentiation to dendritic cells by lactic acid, and secretion of pro-tumorigenic cytokines (i.e., IL-23) (86). Additionally, the metabolic alteration of the TME can affect the function of astrocytes to promote the growth of glioma cells (via release of cholesterol) and the recruitment of immunosuppressive macrophages (87).…”