<br>胶质母细胞瘤干细胞样细胞小细胞外囊泡的蛋白质组学、代谢组学和脂肪酸分析及其在肿瘤异质性中的作用,ACS Nano

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胶质母细胞瘤干细胞样细胞小细胞外囊泡的蛋白质组学、代谢组学和脂肪酸分析及其在肿瘤异质性中的作用
ACS Nano ( IF 15.8 ) Pub Date : 2024-01-11 , DOI: 10.1021/acsnano.3c11427
Tolga Lokumcu _{1,

2} , Murat Iskar ₃ , Martin Schneider ₄ , Dominic Helm ₄ , Glynis Klinke ₅ , Lisa Schlicker _{4,

6} , Frederic Bethke ₁ , Gabriele Müller ₁ , Karsten Richter ₇ , Gernot Poschet ₅ , Emma Phillips ₁ , Violaine Goidts ₁

Affiliation

胶质母细胞瘤是一种致命的脑肿瘤，目前尚无治愈方法。胶质母细胞瘤干细胞样细胞（GSC）的存在导致了疾病的异质性，并使开发有效的疗法具有挑战性。胶质母细胞瘤细胞已被证明通过释放称为细胞外囊泡（EV）的生物纳米结构来影响其环境。在这里，我们研究了 GSC 衍生的纳米 EV （<200 nm）在胶质母细胞瘤异质性、可塑性和侵袭性中的作用，特别关注它们的蛋白质、代谢物和脂肪酸含量。我们发现，源自一种胶质母细胞瘤亚型细胞的条件中小细胞外囊泡（sEV）诱导另一种亚型细胞的转录组学和蛋白质组学变化。我们发现 GSC 衍生的 sEVs 富含蛋白质，这些蛋白质在氨基酸、羧酸和有机酸的跨膜转运、生长因子结合以及与氨基酸、羧酸和糖代谢相关的代谢物中发挥作用。这表明 GSC 衍生的 sEVs 在为邻近的 GSC 提供负责其运输的有价值的代谢物和蛋白质方面具有双重作用。此外，GSC 衍生的 sEVs 富含饱和脂肪酸，而它们各自的细胞富含不饱和脂肪酸，这支持生物货物加载到 sEV 中是一个高度调节的过程，并且 GSC 衍生的 sEVs 可以成为维持胶质母细胞瘤细胞代谢的饱和脂肪酸来源。有趣的是，从前神经和间充质亚型的 GSC 中分离的 sEV 富含特定的蛋白质、代谢物和脂肪酸，表明转录不同的胶质母细胞瘤细胞之间存在分子合作。总之，这项研究揭示了 GSC 衍生的 sEVs 的复杂性，并揭示了它们对肿瘤异质性和胶质母细胞瘤中通常失调的关键细胞过程的潜在贡献。

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

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.

更新日期：2024-01-11

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