ABSTRACT
SorLA, encoded by the gene SORL1, is an intracellular sorting receptor of the VPS10P domain receptor gene family. Although SorLA is best recognized for its ability to shuttle target proteins between intracellular compartments in neurons, recent data suggest that also its microglial expression can be of high relevance for the pathogenesis of brain diseases, including glioblastoma (GBM). Here, we interrogated the impact of SorLA on the functional properties of glioma-associated microglia and macrophages (GAMs). In the GBM microenvironment, GAMs are re-programmed and lose the ability to elicit anti-tumor responses. Instead, they acquire a glioma-supporting phenotype, which is a key mechanism promoting glioma progression. Our re-analysis of published scRNA-seq data from GBM patients revealed that functional phenotypes of GAMs are linked to the level of SORL1 expression, which was further confirmed using in vitro models. Moreover, we demonstrate that SorLA restrains secretion of TNFα from microglia to restrict the inflammatory potential of these cells. Finally, we show that loss of SorLA exacerbates the pro-inflammatory response of microglia in the murine model of glioma and suppresses tumor growth.
Subject(s)
Brain Neoplasms , Glioma , LDL-Receptor Related Proteins , Membrane Transport Proteins , Microglia , Tumor Microenvironment , Tumor Necrosis Factor-alpha , Animals , Humans , Mice , Brain/metabolism , Brain/pathology , Brain Neoplasms/metabolism , Brain Neoplasms/pathology , Brain Neoplasms/genetics , Cell Line, Tumor , Disease Models, Animal , Glioblastoma/metabolism , Glioblastoma/pathology , Glioblastoma/genetics , Glioma/metabolism , Glioma/pathology , Glioma/genetics , Macrophages/metabolism , Membrane Transport Proteins/metabolism , Membrane Transport Proteins/genetics , Microglia/metabolism , Microglia/pathology , Tumor Necrosis Factor-alpha/metabolism , LDL-Receptor Related Proteins/genetics , LDL-Receptor Related Proteins/metabolismABSTRACT
VPS10P (vacuolar protein sorting 10 protein) domain receptors consitute a family of sorting receptors which are responsible for directing their protein cargo into destined subcellular localization. Functions of VPS10P domain receptors have been well-described in neurons, where efficient sorting of proteins is crucial for cell viability. Dysfunctions in neuronal actions of VPS10P domain receptors are linked to disturbances in neuronal plasticity and development of neurodegenerative disorders. VPS10P domain receptors are also crucial for lipid metabolism, mainly through transport of lipolytic enzymes or influencing the uptake of lipoproteins by the cells. Emerging evidence suggests that VPS10P domain receptors can play important roles in immune response evoked by immune or glial cells. They are also key players in pathogenesis of cancers.
