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

IF 9.4 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY EMBO Journal Pub Date : 2024-09-01 Epub Date: 2024-05-08 DOI:10.1038/s44318-024-00103-7
Roma Parikh, Shivang Parikh, Daniella Berzin, Hananya Vaknine, Shai Ovadia, Daniela Likonen, Shoshana Greenberger, Alon Scope, Sharona Elgavish, Yuval Nevo, Inbar Plaschkes, Eran Nizri, Oren Kobiler, Avishai Maliah, Laureen Zaremba, Vishnu Mohan, Irit Sagi, Ruth Ashery-Padan, Yaron Carmi, Chen Luxenburg, Jörg D Hoheisel, Mehdi Khaled, Mitchell P Levesque, Carmit Levy
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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.

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黑色素瘤分泌的黑色素小体可调节肿瘤相关巨噬细胞的多样化。
细胞外囊泡(EVs)是细胞间通信的重要媒介。在这里,我们揭示了黑色素小体进行细胞间通信的一种新模式,黑色素小体是黑色素细胞为运输黑色素而分泌的大型EV。与在接收细胞内分解的小EV不同,黑色素体在接收细胞内保持完整,并获得独特的蛋白质特征,然后可以作为 "二手 "EV进一步转移到另一个细胞。我们的研究表明,通过表皮角质细胞或真皮成纤维细胞传递的黑色素瘤分泌的黑色素小体可被驻留的巨噬细胞进一步吞噬。这一过程会导致巨噬细胞极化为亲肿瘤或亲免疫细胞浸润表型。通过成纤维细胞转移的黑色素小体可携带 AKT1,AKT1 可通过 mTOR 依赖性方式诱导巨噬细胞分泌血管内皮生长因子,促进体内血管生成和转移。在黑色素瘤患者中,与AKT1共定位的巨噬细胞与疾病的侵袭性相关,免疫疗法无反应者的巨噬细胞中富含黑色素体标记。我们的研究结果表明,二手细胞外囊泡介导的相互作用促成了转移龛的形成,阻断巨噬细胞多样化的黑色素体线索有助于阻止黑色素瘤的发展。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
EMBO Journal
EMBO Journal 生物-生化与分子生物学
CiteScore
18.90
自引率
0.90%
发文量
246
审稿时长
1.5 months
期刊介绍: The EMBO Journal has stood as EMBO's flagship publication since its inception in 1982. Renowned for its international reputation in quality and originality, the journal spans all facets of molecular biology. It serves as a platform for papers elucidating original research of broad general interest in molecular and cell biology, with a distinct focus on molecular mechanisms and physiological relevance. With a commitment to promoting articles reporting novel findings of broad biological significance, The EMBO Journal stands as a key contributor to advancing the field of molecular biology.
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