Lipid-Orchestrated Acceleration of Epstein-Barr Virus-Induced B-Cell Lymphoma Via the Secreted Phospholipase A 2 -Mediated Modification of Exosomes
Social Science Research Network(2021)
摘要
Exosomes act as intercellular communicators by transferring protein and microRNA cargoes, yet the role of exosome lipids remains unclear. Here, we show that the pro-tumorigenic action of lymphoma-derived exosomes is augmented via secreted phospholipase A2(sPLA2)-driven lipid metabolism. Hydrolysis of exosomal 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 exosomes were smaller, 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; treatment with sPLA2-modified exosomes reversed this phenotype. Further, sPLA2 expression in human large B-cell lymphomas inversely correlated with patient survival. Overall, the sPLA2-mediated exosome modification promotes tumor development.
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