학술논문
Recycled melanoma-secreted melanosomes regulate tumor-associated macrophage diversification
Document Type
Original Paper
Author
Parikh, Roma; Parikh, Shivang; Berzin, Daniella; Vaknine, Hananya; Ovadia, Shai; Likonen, Daniela; Greenberger, Shoshana; Scope, Alon; Elgavish, Sharona; Nevo, Yuval; Plaschkes, Inbar; Nizri, Eran; Kobiler, Oren; Maliah, Avishai; Zaremba, Laureen; Mohan, Vishnu; Sagi, Irit; Ashery-Padan, Ruth; Carmi, Yaron; Luxenburg, Chen; Hoheisel, Jörg D; Khaled, Mehdi; Levesque, Mitchell P; Levy, Carmit
Source
The EMBO Journal. :1-34
Subject
Language
English
ISSN
1460-2075
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.
Synopsis: Extracellular vesicles (EVs) are known to mediate cell-to-cell communication in various contexts. This study reveals a new mode of intercellular communication involving recycled, “second-hand” EVs that are originally secreted by melanoma cells and drive tumor-associated macrophage diversification.Melanosomes passaged through epidermal keratinocytes or dermal fibroblasts can be further engulfed by resident macrophages.This process polarizes macrophages into pro-tumor or pro-immune cell infiltration phenotypes.Macrophages treated with melanosomes from different source cells exhibit functional diversity.Fibroblasts can transfer melanosomes loaded with AKT1, which promote angiogenesis and metastasis in vivo.Melanoma patients that do not respond to immunotherapy exhibit elevated levels of macrophages containing melanosome markers.
“Second-hand” extracellular vesicles secreted by melanoma cells induce macrophage polarization and diversification after passage through different cell types.
Synopsis: Extracellular vesicles (EVs) are known to mediate cell-to-cell communication in various contexts. This study reveals a new mode of intercellular communication involving recycled, “second-hand” EVs that are originally secreted by melanoma cells and drive tumor-associated macrophage diversification.Melanosomes passaged through epidermal keratinocytes or dermal fibroblasts can be further engulfed by resident macrophages.This process polarizes macrophages into pro-tumor or pro-immune cell infiltration phenotypes.Macrophages treated with melanosomes from different source cells exhibit functional diversity.Fibroblasts can transfer melanosomes loaded with AKT1, which promote angiogenesis and metastasis in vivo.Melanoma patients that do not respond to immunotherapy exhibit elevated levels of macrophages containing melanosome markers.
“Second-hand” extracellular vesicles secreted by melanoma cells induce macrophage polarization and diversification after passage through different cell types.