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Cellular and Molecular Biology

Cell-cell contact-dependent secretion of large-extracellular vesicles from EFNBhigh cancer cells accelerates peritoneal dissemination

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Abstract

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

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 Wt1CreERT2-tdTnu mice to explore the effects of LEVs on PMCs in vivo, and lymphangiogenesis was assessed by qRT-PCR and flow-cytometry.

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

EFNBhigh cancer cells scattered LEVs when they attached to PMCs, which augmented the local reactions of PMC and MΦ (MMT and lymphangiogenesis) and exaggerated peritoneal dissemination.

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Fig. 1: LEVs are released from HT29 cells by the contact with PMCs and MC3T3-E1 cells.
Fig. 2: Ephrin-B mediated RhoA-Rock activation is indispensable for LEV secretion.
Fig. 3: LEVs carry TGF-β1/Akt and EFNBs, which induced MMT in PMCs.
Fig. 4: LEV augments uptake by MΦs, and upregulates immunosuppressive genes.
Fig. 5: LEV exaggerates dissemination and lymphatic invasion of cancer cells.
Fig. 6: LEV induced transdifferentiation of MΦ and PMC to LEC.

Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.

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Acknowledgements

We thank members of the Bioscience Education and Research Support Center (BERSC) of Akita University for technical assistance. This work was supported by JSPS KAKENHI grants (22H02897, 23K18307 to M. Tanaka, 22K07163 to G. Itoh, 21K07090 to S. Kuriyama, 22H04373 to K. Takagane), Takeda Science Foundation grants (to M. Tanaka and G. Itoh), a Research Grant from the Princess Takamatsu cancer Research Fund (19-25123 to M. Tanaka), and Research Project Program of Joint Usage/Research Center at the Institute of Development, Aging and cancer, Tohoku University (G. Itoh).

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Authors and Affiliations

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

    Kaito Hayashi, Kurara Takagane, Go Itoh, Sei Kuriyama & Masamitsu Tanaka

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

    Kaito Hayashi & Masaru Mizuno

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

    Souichi Koyota & Kenji Meguro

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

    Yiwei Ling

  5. 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

    Tatsuya Abé

  6. 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

    Riuko Ohashi

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

    Masakazu Yashiro

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  1. Kaito Hayashi
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  2. Kurara Takagane
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  3. Go Itoh
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  10. Masakazu Yashiro
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  11. Masaru Mizuno
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  12. Masamitsu Tanaka
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Contributions

MT designed the study. MM conceptually contributed to the work. KH, KT, GI, S Kuriyama, MT performed experiments and data analysis. KH, S Koyota, TM, YL, TA and RO performed bioinformatics analysis of scRNA-seq data. KT performed flow cytometric analysis and IHC. MT performed pathological evaluation. MY provided cell materials. KH prepared the manuscript. MT made the final critical revision of the manuscript.

Corresponding author

Correspondence to Masamitsu Tanaka.

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The authors declare no competing interests.

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The study was conducted in accordance with the principles of the Declaration of Helsinki principles. This study was approved by the Akita University Ethics Committee (approval number a-1-3175, Akita, Japan) and Osaka City University Ethics Committee (approval number 2756, Osaka, Japan).

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Hayashi, K., Takagane, K., Itoh, G. et al. Cell-cell contact-dependent secretion of large-extracellular vesicles from EFNBhigh cancer cells accelerates peritoneal dissemination. Br J Cancer (2024). https://doi.org/10.1038/s41416-024-02783-8

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