Cell-cell contact-dependent secretion of large-extracellular vesicles from EFNB

Journal

British journal of cancer
ISSN: 1532-1827
Titre abrégé: Br J Cancer
Pays: England
ID NLM: 0370635

Informations de publication

Date de publication:
13 Jul 2024
Historique:
received: 22 03 2024
accepted: 25 06 2024
revised: 19 06 2024
medline: 14 7 2024
pubmed: 14 7 2024
entrez: 13 7 2024
Statut: aheadofprint

Résumé

Large non-apoptotic vesicles released from the plasma membrane protrusions are classified as large-EVs (LEVs). However, the triggers of LEV secretion and their functions in tumors remain unknown. Coculture system of cancer cells, peritoneal mesothelial cells (PMCs), and macrophages (MΦs) was conducted to observe cell-cell contact-mediated LEV secretion. Lineage tracing of PMCs was performed using Wt1 In peritoneal dissemination, cancer cells expressing Ephrin-B (EFNB) secreted LEVs upon the contact with PMCs expressing ephrin type-B (EphB) receptors, which degraded mesothelial barrier by augmenting mesothelial-mesenchymal transition. LEVs were incorporated in subpleural MΦs, and these MΦs transdifferentiated into lymphatic endothelial cells (LEC) and integrated into the lymphatic vessels. LEC differentiation was also induced in PMCs by interacting with LEV-treated MΦs, which promoted lymphangiogenesis. Mechanistically, activation of RhoA-ROCK pathway through EFNB reverse signaling induced LEV secretion. EFNBs on LEVs activated EphB forward signaling in PMC and MΦs, activating Akt, ERK and TGF-β1 pathway, which were indispensable for causing MMT and LEC differentiation. LEVs accelerated peritoneal dissemination and lymphatic invasions by cancer cells. Blocking of EFNBs on LEVs using EphB-Fc-fusion protein attenuated these events. EFNB

Sections du résumé

BACKGROUND BACKGROUND
Large non-apoptotic vesicles released from the plasma membrane protrusions are classified as large-EVs (LEVs). However, the triggers of LEV secretion and their functions in tumors remain unknown.
METHODS METHODS
Coculture system of cancer cells, peritoneal mesothelial cells (PMCs), and macrophages (MΦs) was conducted to observe cell-cell contact-mediated LEV secretion. Lineage tracing of PMCs was performed using Wt1
RESULTS RESULTS
In peritoneal dissemination, cancer cells expressing Ephrin-B (EFNB) secreted LEVs upon the contact with PMCs expressing ephrin type-B (EphB) receptors, which degraded mesothelial barrier by augmenting mesothelial-mesenchymal transition. LEVs were incorporated in subpleural MΦs, and these MΦs transdifferentiated into lymphatic endothelial cells (LEC) and integrated into the lymphatic vessels. LEC differentiation was also induced in PMCs by interacting with LEV-treated MΦs, which promoted lymphangiogenesis. Mechanistically, activation of RhoA-ROCK pathway through EFNB reverse signaling induced LEV secretion. EFNBs on LEVs activated EphB forward signaling in PMC and MΦs, activating Akt, ERK and TGF-β1 pathway, which were indispensable for causing MMT and LEC differentiation. LEVs accelerated peritoneal dissemination and lymphatic invasions by cancer cells. Blocking of EFNBs on LEVs using EphB-Fc-fusion protein attenuated these events.
CONCLUSIONS CONCLUSIONS
EFNB

Identifiants

DOI: 10.1038/s41416-024-02783-8 PMID: 39003372
pubmed: 39003372
doi: 10.1038/s41416-024-02783-8
pii: 10.1038/s41416-024-02783-8
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Subventions

Organisme : MEXT | Japan Society for the Promotion of Science (JSPS)
ID : 22H02897
Organisme : MEXT | Japan Society for the Promotion of Science (JSPS)
ID : 23K18307
Organisme : MEXT | Japan Society for the Promotion of Science (JSPS)
ID : 22H04373
Organisme : MEXT | Japan Society for the Promotion of Science (JSPS)
ID : 22K07163
Organisme : MEXT | Japan Society for the Promotion of Science (JSPS)
ID : 21K07090

Informations de copyright

© 2024. The Author(s), under exclusive licence to Springer Nature Limited.

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Auteurs

Kaito Hayashi (K)

Department of Molecular Medicine and Biochemistry, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, 010-8543, Japan.
Department of Pediatric Surgery, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, 010-8543, Japan.

Kurara Takagane (K)

Department of Molecular Medicine and Biochemistry, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, 010-8543, Japan.

Go Itoh (G)

Department of Molecular Medicine and Biochemistry, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, 010-8543, Japan.

Sei Kuriyama (S)

Department of Molecular Medicine and Biochemistry, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, 010-8543, Japan.

Souichi Koyota (S)

Bioscience Education and Research Support Center, Akita University, 1-1-1 Hondo, Akita, 010-8543, Japan.

Kenji Meguro (K)

Bioscience Education and Research Support Center, Akita University, 1-1-1 Hondo, Akita, 010-8543, Japan.

Yiwei Ling (Y)

Medical AI Center, Niigata University School of Medicine, Niigata University Life Innovation Hub, 2-5274, Gakkocho-dori, Chuo-ku, Niigata, 951-8514, Japan.

Tatsuya Abé (T)

Division of Oral Pathology, Faculty of Dentistry & Graduate School of Medical and Dental Sciences, Niigata University, 1-757 Asahimachi-dori, Chuo-ku, Niigata, 951-8510, Japan.

Riuko Ohashi (R)

Divisions of Molecular and Diagnostic Pathology, Graduate School of Medical and Dental Sciences, Niigata University, 1-757 Asahimachi-dori, Chuo-ku, Niigata, 951-8510, Japan.

Masakazu Yashiro (M)

Department of Molecular Oncology and Therapeutics, Osaka Metropolitan University Graduate School of Medicine, 1-4-3 Asahimachi, Abeno-ku, Osaka, 545-8545, Japan.

Masaru Mizuno (M)

Department of Pediatric Surgery, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, 010-8543, Japan.

Masamitsu Tanaka (M)

Department of Molecular Medicine and Biochemistry, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, 010-8543, Japan. mastanak@med.akita-u.ac.jp.
ORCID: 0000-0002-4823-9737

Classifications MeSH