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

doi:10.1016/j.cmet.2022.02.011

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

研究成果: ジャーナルへの寄稿 › 記事 › 査読

39 被引用数 (Scopus)

抄録

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.

本文言語	英語
ページ（範囲）	615-633.e8
ジャーナル	Cell Metabolism
巻	34
号	4
DOI	https://doi.org/10.1016/j.cmet.2022.02.011
出版ステータス	出版済み - 5 4月 2022
外部発表	はい

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10.1016/j.cmet.2022.02.011

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Kudo, K., Miki, Y., Carreras, J., Nakayama, S., Nakamoto, Y., Ito, M., Nagashima, E., Yamamoto, K., Higuchi, H., Morita, S. Y., Inoue, A., Aoki, J., Ando, K., Nakamura, N., Murakami, M., & Kotani, A. (2022). Secreted phospholipase A₂ modifies extracellular vesicles and accelerates B cell lymphoma. Cell Metabolism, 34(4), 615-633.e8. https://doi.org/10.1016/j.cmet.2022.02.011

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title = "Secreted phospholipase A2 modifies extracellular vesicles and accelerates B cell lymphoma",

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",

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

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year = "2022",

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day = "5",

doi = "10.1016/j.cmet.2022.02.011",

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Kudo, K, Miki, Y, Carreras, J, Nakayama, S, Nakamoto, Y, Ito, M, Nagashima, E, Yamamoto, K, Higuchi, H, Morita, SY, Inoue, A, Aoki, J, Ando, K, Nakamura, N, Murakami, M & Kotani, A 2022, 'Secreted phospholipase A₂ modifies extracellular vesicles and accelerates B cell lymphoma', Cell Metabolism, vol. 34, no. 4, pp. 615-633.e8. https://doi.org/10.1016/j.cmet.2022.02.011

TY - JOUR

T1 - Secreted phospholipase A2 modifies extracellular vesicles and accelerates B cell lymphoma

AU - Kudo, Kai

AU - Miki, Yoshimi

AU - Carreras, Joaquim

AU - Nakayama, Shunya

AU - Nakamoto, Yasushi

AU - Ito, Masatoshi

AU - Nagashima, Etsuko

AU - Yamamoto, Kei

AU - Higuchi, Hiroshi

AU - Morita, Shin ya

AU - Inoue, Asuka

AU - Aoki, Junken

AU - Ando, Kiyoshi

AU - Nakamura, Naoya

AU - Murakami, Makoto

AU - Kotani, Ai

PY - 2022/4/5

Y1 - 2022/4/5

N2 - 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.

AB - 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.

KW - EBV Lymphoma

KW - extracellular vesicle

KW - lipid mediator

KW - sPLA₂

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SN - 1550-4131

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SP - 615-633.e8

JO - Cell Metabolism

JF - Cell Metabolism

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ER -

Secreted phospholipase A2 modifies extracellular vesicles and accelerates B cell lymphoma

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Secreted phospholipase A₂ modifies extracellular vesicles and accelerates B cell lymphoma