Recycled melanoma-secreted melanosomes regulate tumor-associated macrophage diversification

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 LuxenburgJörg D. Hoheisel, Mehdi Khaled, Mitchell P. Levesque, Carmit Levy

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

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.

Original languageEnglish
Pages (from-to)3553-3586
Number of pages34
JournalEMBO Journal
Volume43
Issue number17
DOIs
StatePublished - 2 Sep 2024
Externally publishedYes

Keywords

  • Angiogenesis
  • Cell-to-Cell-Transfer
  • Heterogeneity
  • Melanosomes
  • Tumor Associated Macrophages

ASJC Scopus subject areas

  • General Neuroscience
  • Molecular Biology
  • General Biochemistry, Genetics and Molecular Biology
  • General Immunology and Microbiology

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