Recycled melanoma-secreted melanosomes regulate tumor-associated macrophage diversification.

Autor:	Parikh R; Department of Human Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, 69978, Israel., Parikh S; Department of Human Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, 69978, Israel.; The Ragon Institute of Mass General, Massachusetts Institute of Technology (MIT), and Harvard, MA 02139, Cambridge, USA., Berzin D; Institute of Pathology, Sheba Medical Center, Tel Hashomer, 52621, Israel., Vaknine H; Institute of Pathology, E. Wolfson Medical Center, Holon, 58100, Israel., Ovadia S; Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine and Sagol School of Neurosciences, Tel Aviv University, Tel Aviv, 69978, Israel., Likonen D; Institute of Pathology, Sheba Medical Center, Tel Hashomer, 52621, Israel., Greenberger S; Institute of Pathology, Sheba Medical Center, Tel Hashomer, 52621, Israel., Scope A; The Kittner Skin Cancer Screening and Research Institute, Sheba Medical Center and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel., Elgavish S; Info-CORE, Bioinformatics Unit of the I-CORE at the Hebrew University of Jerusalem and Hadassah Medical Center, Jerusalem, 91120, Israel., Nevo Y; Info-CORE, Bioinformatics Unit of the I-CORE at the Hebrew University of Jerusalem and Hadassah Medical Center, Jerusalem, 91120, Israel., Plaschkes I; Info-CORE, Bioinformatics Unit of the I-CORE at the Hebrew University of Jerusalem and Hadassah Medical Center, Jerusalem, 91120, Israel., Nizri E; Department of Dermatology, Tel Aviv Sourasky (Ichilov) Medical Center, Tel Aviv, 6423906, Israel.; Sackler School of Medicine, Tel Aviv University, Tel Aviv, 69978, Israel., Kobiler O; Department of Clinical Microbiology and Immunology, Sackler School of Medicine, Tel Aviv Universitygrid.12136.37, Tel Aviv, Israel., Maliah A; Department of Human Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, 69978, Israel., Zaremba L; Division of Functional Genome Analysis, German Cancer Research Center (DKFZ), Heidelberg, Germany., Mohan V; Department of Biological Regulation, Weizmann Institute of Science, Rehovot, 7610001, Israel., Sagi I; Department of Biological Regulation, Weizmann Institute of Science, Rehovot, 7610001, Israel., Ashery-Padan R; Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine and Sagol School of Neurosciences, Tel Aviv University, Tel Aviv, 69978, Israel., Carmi Y; Department of Pathology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, 69978, Israel., Luxenburg C; Cell and Developmental Biology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, 69978, Israel., Hoheisel JD; Division of Functional Genome Analysis, German Cancer Research Center (DKFZ), Heidelberg, Germany., Khaled M; INSERM 1279, Gustave Roussy, Université Paris-Saclay, Villejuif, France., Levesque MP; Department of Dermatology, University of Zurich, University Hospital Zurich, Wagistrasse 18, CH-8952, Schlieren, Switzerland., Levy C; Department of Human Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, 69978, Israel. carmitlevy@post.tau.ac.il.
Jazyk:	angličtina
Zdroj:	The EMBO journal [EMBO J] 2024 Sep; Vol. 43 (17), pp. 3553-3586. Date of Electronic Publication: 2024 May 08.
DOI:	10.1038/s44318-024-00103-7
Abstrakt:	Extracellular vesicles (EVs) are important mediators of communication between cells. Here, we reveal a new mode of intercellular communication by melanosomes, large EVs secreted by melanocytes for melanin transport. Unlike small EVs, which are disintegrated within the receiver cell, melanosomes stay intact within them, gain a unique protein signature, and can then be further transferred to another cell as "second-hand" EVs. We show that melanoma-secreted melanosomes passaged through epidermal keratinocytes or dermal fibroblasts can be further engulfed by resident macrophages. This process leads to macrophage polarization into pro-tumor or pro-immune cell infiltration phenotypes. Melanosomes that are transferred through fibroblasts can carry AKT1, which induces VEGF secretion from macrophages in an mTOR-dependent manner, promoting angiogenesis and metastasis in vivo. In melanoma patients, macrophages that are co-localized with AKT1 are correlated with disease aggressiveness, and immunotherapy non-responders are enriched in macrophages containing melanosome markers. Our findings suggest that interactions mediated by second-hand extracellular vesicles contribute to the formation of the metastatic niche, and that blocking the melanosome cues of macrophage diversification could be helpful in halting melanoma progression. (© 2024. The Author(s).)
Databáze:	MEDLINE
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