Recycled melanoma-secreted melanosomes regulate tumor-associated macrophage diversification
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44318_2024_Article_103.pdf
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Author(s)
Parikh, Roma
Parikh, Shivang
Berzin, Daniella
Vaknine, Hananya
Ovadia, Shai
Likonen, Daniela
Greenberger, Shoshana
Scope, Alon
Elgavish, Sharona
Nevo, Yuval
Date Issued
May 8, 2024
Journal
The EMBO Journal
Publisher
Springer Science and Business Media LLC
Citation
Parikh, Roma, Parikh, Shivang, Berzin, Daniella, Vaknine, Hananya, Ovadia, Shai et al. 2024. "Recycled melanoma-secreted melanosomes regulate tumor-associated macrophage diversification." The EMBO Journal.
Version
Final published version
Abstract
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.
MIT Department
Ragon Institute of MGH, MIT and Harvard
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Creative Commons Attribution
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DOI of Published Version
https://doi.org/10.1038/s44318-024-00103-7
