TY - JOUR
T1 - Recycled melanoma-secreted melanosomes regulate tumor-associated macrophage diversification
AU - Parikh, Roma
AU - Parikh, Shivang
AU - Berzin, Daniella
AU - Vaknine, Hananya
AU - Ovadia, Shai
AU - Likonen, Daniela
AU - Greenberger, Shoshana
AU - Scope, Alon
AU - Elgavish, Sharona
AU - Nevo, Yuval
AU - Plaschkes, Inbar
AU - Nizri, Eran
AU - Kobiler, Oren
AU - Maliah, Avishai
AU - Zaremba, Laureen
AU - Mohan, Vishnu
AU - Sagi, Irit
AU - Ashery-Padan, Ruth
AU - Carmi, Yaron
AU - Luxenburg, Chen
AU - Hoheisel, Jörg D.
AU - Khaled, Mehdi
AU - Levesque, Mitchell P.
AU - Levy, Carmit
N1 - Publisher Copyright:
© The Author(s) 2024.
PY - 2024/9/2
Y1 - 2024/9/2
N2 - 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.
AB - 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.
KW - Angiogenesis
KW - Cell-to-Cell-Transfer
KW - Heterogeneity
KW - Melanosomes
KW - Tumor Associated Macrophages
UR - http://www.scopus.com/inward/record.url?scp=85192348745&partnerID=8YFLogxK
U2 - 10.1038/s44318-024-00103-7
DO - 10.1038/s44318-024-00103-7
M3 - Article
C2 - 38719996
AN - SCOPUS:85192348745
SN - 0261-4189
VL - 43
SP - 3553
EP - 3586
JO - EMBO Journal
JF - EMBO Journal
IS - 17
ER -