Secreted phospholipase A2 modifies extracellular vesicles and accelerates B cell lymphoma
Secreted phospholipase A2 modifies extracellular vesicles and accelerates B cell lymphoma
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DOI：
10.1016/j.cmet.2022.02.011
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发表时间：
2022-04-05
期刊：
影响因子：
29
通讯作者：
Kotani，Ai
中科院分区：
文献类型：
--
作者：
Kudo，Kai;Miki，Yoshimi;Kotani，Ai
包括外泌体在内的细胞外囊泡（EV）通过转移蛋白质和microRNA货物充当细胞间通讯者，但EV脂质的作用仍不清楚。在这里，我们表明，淋巴瘤衍生的EV的促肿瘤作用是通过分泌型磷脂酶A2（sPLA2）驱动的脂质代谢增强。EV磷脂水解组X sPLA2，这是诱导巨噬细胞的EB病毒（EBV）淋巴瘤，增加生产的脂肪酸，溶血磷脂，及其代谢产物。sPLA2处理的EV较小且自聚集，显示出更好的摄取，并增加了肿瘤相关巨噬细胞中的细胞因子表达和脂质介质信号传导。内源性sPLA2的药理学抑制抑制EBV感染的人源化小鼠中淋巴瘤的生长，而用sPLA2修饰的EV治疗逆转了这种表型。此外，sPLA 2在人类大B细胞淋巴瘤中的表达与患者的生存率呈负相关。总的来说，sPLA2介导的EV修饰促进肿瘤发展，突出了EV作为sPLA2的细胞外水解平台的非经典机制作用。
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 sPLA2suppressed lymphoma growth in EBV-infected humanized mice, while treatment with sPLA2-modified EVs reversed this phenotype. Furthermore, sPLA2expression 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.