Proteomic, Metabolomic, and Fatty Acid Profiling of Small Extracellular Vesicles from Glioblastoma Stem-Like Cells and Their Role in Tumor Heterogeneity

被引:13
作者
Lokumcu, Tolga [1 ,2 ]
Iskar, Murat [3 ]
Schneider, Martin [4 ]
Helm, Dominic [4 ]
Klinke, Glynis [5 ]
Schlicker, Lisa [4 ,6 ]
Bethke, Frederic [1 ]
Mu''ller, Gabriele [1 ]
Richter, Karsten [7 ]
Poschet, Gernot [5 ]
Phillips, Emma [1 ]
Goidts, Violaine [1 ]
机构
[1] German Canc Res Ctr, Brain Tumor Translat Targets, D-69120 Heidelberg, Germany
[2] Heidelberg Univ, Fac Biosci, D-69120 Heidelberg, Germany
[3] Friedrich Miescher Inst Biomed Res, CH-4058 Basel, Switzerland
[4] German Canc Res Ctr, Prote Core Facil, D-69120 Heidelberg, Germany
[5] Heidelberg Univ, Ctr Organismal Studies, Metabol Core Technol Platform, D-69120 Heidelberg, Germany
[6] German Canc Res Ctr, Div Tumor Metab & Microenvironm, D-69120 Heidelberg, Germany
[7] German Canc Res Ctr, Core Facil Electron Microscopy, D-69120 Heidelberg, Germany
关键词
small extracellular vesicles; exosomes; metabolomics; proteomics; fatty acids; glioblastoma; glioblastoma stem-like cells; GLUTAMINE-METABOLISM; INTRATUMORAL HETEROGENEITY; GLYCOLYTIC METABOLISM; PHOSPHATIDIC-ACID; CO-DEPENDENCY; CANCER-CELLS; EXPRESSION; BRAIN; MICROVESICLES; METHYLGLYOXAL;
D O I
10.1021/acsnano.3c11427
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
Glioblastoma is a deadly brain tumor for which there is no cure. The presence of glioblastoma stem-like cells (GSCs) contributes to the heterogeneous nature of the disease and makes developing effective therapies challenging. Glioblastoma cells have been shown to influence their environment by releasing biological nanostructures known as extracellular vesicles (EVs). Here, we investigated the role of GSC-derived nanosized EVs (<200 nm) in glioblastoma heterogeneity, plasticity, and aggressiveness, with a particular focus on their protein, metabolite, and fatty acid content. We showed that conditioned medium and small extracellular vesicles (sEVs) derived from cells of one glioblastoma subtype induced transcriptomic and proteomic changes in cells of another subtype. We found that GSC-derived sEVs are enriched in proteins playing a role in the transmembrane transport of amino acids, carboxylic acids, and organic acids, growth factor binding, and metabolites associated with amino acid, carboxylic acid, and sugar metabolism. This suggests a dual role of GSC-derived sEVs in supplying neighboring GSCs with valuable metabolites and proteins responsible for their transport. Moreover, GSC-derived sEVs were enriched in saturated fatty acids, while their respective cells were high in unsaturated fatty acids, supporting that the loading of biological cargos into sEVs is a highly regulated process and that GSC-derived sEVs could be sources of saturated fatty acids for the maintenance of glioblastoma cell metabolism. Interestingly, sEVs isolated from GSCs of the proneural and mesenchymal subtypes are enriched in specific sets of proteins, metabolites, and fatty acids, suggesting a molecular collaboration between transcriptionally different glioblastoma cells. In summary, this study revealed the complexity of GSC-derived sEVs and unveiled their potential contribution to tumor heterogeneity and critical cellular processes commonly deregulated in glioblastoma.
引用
收藏
页码:2500 / 2519
页数:20
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