Secreted phospholipase A2 modifies extracellular vesicles and accelerates B cell lymphoma

Kai Kudo, Yoshimi Miki, Joaquim Carreras, Shunya Nakayama, Yasushi Nakamoto, Masatoshi Ito, Etsuko Nagashima, Kei Yamamoto, Hiroshi Higuchi, Shin ya Morita, Asuka Inoue, Junken Aoki, Kiyoshi Ando, Naoya Nakamura, Makoto Murakami, Ai Kotani

Research output: Contribution to journalArticlepeer-review

35 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)615-633.e8
JournalCell Metabolism
Volume34
Issue number4
DOIs
Publication statusPublished - 5 Apr 2022
Externally publishedYes

Keywords

  • EBV Lymphoma
  • extracellular vesicle
  • lipid mediator
  • sPLA₂

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