Search

Glioblastoma (GBM) is a malignancy dominated by the infiltration of tumor-associated myeloid cells (TAMCs). Examination of TAMC metabolic phenotypes in mouse models and patients with GBM identified the de novo creatine metabolic pathway as a hallmark of TAMCs. Multi-omics analyses revealed that TAMCs surround the hypoxic peri-necrotic regions of GBM and express the creatine metabolic enzyme glycine amidinotransferase (GATM). Conversely, GBM cells located within these same regions are uniquely specific in expressing the creatine transporter (SLC6A8). We hypothesized that TAMCs provide creatine to tumors, promoting GBM progression. Isotopic tracing demonstrated that TAMC-secreted creatine is taken up by tumor cells. Creatine supplementation protected tumors from hypoxia-induced stress, which was abrogated with genetic ablation or pharmacologic inhibition of SLC6A8. Lastly, inhibition of creatine transport using the clinically relevant compound, RGX-202-01, blunted tumor growth and enhanced radiation therapy in vivo. This work highlights that myeloid-to-tumor transfer of creatine promotes tumor growth in the hypoxic niche. [Display omitted] • Myeloid cells in the hypoxic niche of GBM upregulate de novo creatine biosynthesis • TAMC-generated creatine is taken up by GBM cells under hypoxic stress • Creatine uptake by GBM tissue supports its growth, survival, and stem cell phenotypes • Inhibition of creatine uptake presents a potential therapeutic strategy for GBM Glioblastoma (GBM), a deadly CNS malignancy, features profoundly hypoxic niches. Rashidi and Billingham et al. report that within these niches, myeloid cells upregulate creatine biosynthesis and "feed" it to tumor cells, which upregulate creatine import under metabolic stress. Therapeutic targeting of this axis provides a potential avenue for GBM treatment. [ABSTRACT FROM AUTHOR]

Abstract Although radiotherapy has been established as a major therapeutic modality for glioma, radical new avenues are critically needed to prevent inevitable tumor recurrence. Herein, we utilized a magnetic nanoparticle-based platform with cationic polymer modification to promote radiotherapy for glioma treatment. We found that the nanoplatform induced cytotoxicity to glioma cells under radiation as well as promoting significant survival benefits in both immunocompetent and aythmic mice with glioma. Utilizing the magnetic properties of the nanoparticles, we were able to ascertain that myeloid derived suppressor cells (MDSC) were taking up nanoparticles in the brain tumor. The observed efficacy was attributed to destruction of glioma cells as well as MDSCs repolarization from immunosuppressive phenotype to a pro-inflammatory phenotype, which promoted antitumor effects and synergistically promoted radio-therapeutic effects. Our nanoparticles provide a robust dual-targeting platform for glioma radiotherapy by simultaneous eradication of tumor cells and manipulation of myeloid phenotypes in the central nervous system. Graphical Abstract We designed a zinc-doped iron oxide nanoparticle with cationic polymer surface as a radioenhancer that can target both cancer cells and the immunosuppressive tumor microenvironment to boost synergistic effects for radiotherapy of brain cancer. MDSCs were partially jeopardized as well as repolarized into a pro-inflammatory phenotype generating antitumor effect with the nanoparticles post radiation treatment. This platform provides a robust approach for effective glioma radiotherapy by simultaneous eradication of tumor cells and manipulation of myeloid phenotype in the central nervous system. Unlabelled Image [ABSTRACT FROM AUTHOR]

Summary The mechanisms by which regulatory T cells (Tregs) migrate to and function within the hypoxic tumor microenvironment are unclear. Our studies indicate that specific ablation of hypoxia-inducible factor 1α (HIF-1α) in Tregs results in enhanced CD8+ T cell suppression versus wild-type Tregs under hypoxia, due to increased pyruvate import into the mitochondria. Importantly, HIF-1α-deficient Tregs are minimally affected by the inhibition of lipid oxidation, a fuel that is critical for Treg metabolism in tumors. Under hypoxia, HIF-1α directs glucose away from mitochondria, leaving Tregs dependent on fatty acids for mitochondrial metabolism within the hypoxic tumor. Indeed, inhibition of lipid oxidation enhances the survival of mice with glioma. Interestingly, HIF-1α-deficient-Treg mice exhibit significantly enhanced animal survival in a murine model of glioma, due to their stymied migratory capacity, explaining their reduced abundance in tumor-bearing mice. Thus HIF-1α acts as a metabolic switch for Tregs between glycolytic-driven migration and oxidative phosphorylation-driven immunosuppression. Graphical Abstract Highlights • HIF-1α acts as a switch to promote Treg migration at the cost of immunosuppression • Glycolysis promotes Treg migration, while OXPHOS promotes Treg immunosuppression • Tregs catabolize free fatty acids for immunosuppression within hypoxic brain tumors Miska et al. demonstrate that regulatory T cell (Treg)-specific depletion of HIF-1α promotes enhanced immune suppression at the cost of migration under hypoxic conditions. Within the hypoxic brain-tumor environment, Tregs are uniquely able to metabolize extracellular free fatty acids to promote their immunosuppressive functionality, which can be targeted in vivo. [ABSTRACT FROM AUTHOR]

The membrane-bound receptor for platelet-derived growth factor A (PDGFRα) is crucial for controlling the production of oligodendrocytes (OLs) for myelination, but regulation of its activity during OL differentiation is largely unknown. We have examined the effect of increased sulfated content of galactosylceramides (sulfatides) on the regulation of PDGFRα in multipotential neural precursors (NPs) that are deficient in arylsulfatase A (ASA) activity. This enzyme is responsible for the lysosomal hydrolysis of sulfatides. We show that sulfatide accumulation significantly impacts the formation of OLs via deregulation of PDGFRα function. PDGFRα is less associated with detergent-resistant membranes in ASA-deficient cells and showed a significant decrease in AKT phosphorylation. Rescue experiments with ASA showed a normalization of the ratio of long versus short sulfatides, restored PDGFRα levels, corrected its localization to detergent-resistant membranes, increased AKT phosphorylation, and normalized the production of OLs in ASA-deficient NPs. Moreover, our studies identified a novel mechanism that regulates the secretion of PDGFRα in NPs, in glial cells, and in the brain cortex via exosomal shedding. Our study provides a first step in understanding the role of sulfatides in regulating PDGFRα levels in OLs and its impact in myelination. [ABSTRACT FROM AUTHOR]