Secreted phospholipase A2 modifies extracellular vesicles and accelerates B cell lymphoma

  • Cell Metab. 2022 Apr 5;34(4):615-633.e8. doi: 10.1016/j.cmet.2022.02.011.
Kai Kudo  1 ,  Yoshimi Miki  2 ,  Joaquim Carreras  3 ,  Shunya Nakayama  4 ,  Yasushi Nakamoto  1 ,  Masatoshi Ito  5 ,  Etsuko Nagashima  1 ,  Kei Yamamoto  6 ,  Hiroshi Higuchi  7 ,  Shin-Ya Morita  8 ,  Asuka Inoue  9 ,  Junken Aoki  10 ,  Kiyoshi Ando  11 ,  Naoya Nakamura  3 ,  Makoto Murakami  12 ,  Ai Kotani  13
Affiliations
  • 1. Department of Innovative Medical Science, Tokai University School of Medicine, Isehara, Japan; Division of Hematological Malignancy, Institute of Medical Sciences, Tokai University, Isehara, Japan.
  • 2. Laboratory of Microenvironmental Metabolic Health Sciences Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
  • 3. Department of Pathology, Tokai University School of Medicine, Isehara, Japan.
  • 4. Department of Innovative Medical Science, Tokai University School of Medicine, Isehara, Japan; Division of Hematological Malignancy, Institute of Medical Sciences, Tokai University, Isehara, Japan; Department of Hematology and Oncology, Tokai University School of Medicine, Isehara, Japan.
  • 5. Support Center for Medical Research and Education, Tokai University School of Medicine, Isehara, Japan.
  • 6. Division of Bioscience and Bioindustry, Graduate School of Technology, Industrial and Social Sciences, Tokushima University, Tokushima, Japan.
  • 7. Center for Cancer Immunology, Cutaneous Biology Research Center, Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
  • 8. Department of Pharmacy, Shiga University of Medical Science Hospital, Otsu, Japan.
  • 9. Department of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.
  • 10. Department of Health Chemistry, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan.
  • 11. Department of Hematology and Oncology, Tokai University School of Medicine, Isehara, Japan.
  • 12. Laboratory of Microenvironmental Metabolic Health Sciences Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. Electronic address: [email protected].
  • 13. Department of Innovative Medical Science, Tokai University School of Medicine, Isehara, Japan; Division of Hematological Malignancy, Institute of Medical Sciences, Tokai University, Isehara, Japan. Electronic address: [email protected].
PMID: 35294862 DOI: 10.1016/j.cmet.2022.02.011
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.

Keywords
EBV Lymphoma; extracellular vesicle; lipid mediator; sPLA₂.
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