Abstract：
Extracellular vesicles (EVs) including exosomes act as intercellular communicators by transferring protein and microRNA cargoes, yet the role of EV lipids remains unclear. Here, we show that the pro-tumorigenic action of lymphoma-derived EVs is augmented via secreted phospholipase A2 (sPLA2)-driven lipid metabolism. Hydrolysis of EV phospholipids by group X sPLA2, which was induced in macrophages of Epstein-Barr virus (EBV) lymphoma, increased the production of fatty acids, lysophospholipids, and their metabolites. sPLA2-treated EVs were smaller and self-aggregated, showed better uptake, and increased cytokine expression and lipid mediator signaling in tumor-associated macrophages. Pharmacological inhibition of endogenous sPLA2 suppressed lymphoma growth in EBV-infected humanized mice, while treatment with sPLA2-modified EVs reversed this phenotype. Furthermore, sPLA2 expression in human large B cell lymphomas inversely correlated with patient survival. Overall, the sPLA2-mediated EV modification promotes tumor development, highlighting a non-canonical mechanistic action of EVs as an extracellular hydrolytic platform of sPLA2.
摘要：
包括外泌体在内的细胞外囊泡（EV）通过转移蛋白质和microRNA货物充当细胞间通信者，然而,EV脂质的作用尚不清楚.这里,我们表明,淋巴瘤衍生的EV的促肿瘤发生作用是通过分泌的磷脂酶A2(sPLA2)驱动的脂质代谢而增强的.在EB病毒（EBV）淋巴瘤的巨噬细胞中诱导的X组sPLA2水解EV磷脂，增加了脂肪酸的产量，溶血磷脂，以及它们的代谢物.SPLA2处理的电动汽车较小，并且是自聚集的，表现出更好的摄取，以及肿瘤相关巨噬细胞中细胞因子表达和脂质介质信号增加。内源性sPLA2的药理学抑制抑制了EBV感染的人源化小鼠的淋巴瘤生长，而用sPLA2修饰的EV治疗逆转了这种表型。此外，人类大B细胞淋巴瘤中sPLA2的表达与患者生存率呈负相关。总的来说,sPLA2介导的EV修饰促进肿瘤发展，强调电动汽车作为sPLA2的细胞外水解平台的非规范机制作用。
