Melanoma-Derived Exosomal miR-125b-5p Educates Tumor Associated Macrophages (TAMs) by Targeting Lysosomal Acid Lipase A (LIPA).

Tom Wersig,Dennis Gerloff,Jana Lützkendorf,Cord Sunderkötter,Karsten Mäder,Rose K.C Moritz,Lutz P Müller

doi:10.3390/cancers12020464

Tom Wersig, Dennis Gerloff + Show 5 more

Open Access

https://doi.org/10.3390/cancers12020464

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Journal: Cancers	Publication Date: Feb 17, 2020
Citations: 76	License type: CC BY 4.0

Affiliation: Martin Luther University Halle-Wittenberg

Abstract

Tumor-associated macrophages (TAMs) are the most abundant immune cells in the tumor microenvironment, promoting tumor initiation, growth, progression, metastasis, and immune evasion. Recently it was shown that cancer cell-derived exosomes induce a tumor-promoting phenotype in TAMs. Exosome-loaded proteins, DNA, and RNAs may contribute to the macrophage reprogramming. However, the exact mediators and mechanisms, particularly in melanoma, are not known. In this study we examined the effects of cutaneous melanoma-derived exosomes on macrophage function and the underlying mechanisms. First, we showed that exposure to melanoma exosomes induces a tumor-promoting TAM phenotype in macrophages. Sequencing revealed enrichment for several miRNAs including miR-125b-5p in cutaneous melanoma exosomes. We showed that miR-125b-5p is delivered to macrophages by melanoma exosomes and partially induces the observed tumor-promoting TAM phenotype. Finally, we showed that miR-125b-5p targets the lysosomal acid lipase A (LIPA) in macrophages, which in turn contributes to their phenotype switch and promotes macrophage survival. Thus, our data show for the first time that miR-125b-5p transferred by cutaneous melanoma-derived exosomes induces a tumor-promoting TAM phenotype in macrophages.

Highlights

Exosomes are small cell-derived membrane nanovesicles of about 50–200 nm in diameter, loaded with proteins, DNA, and coding and non-coding RNAs, e.g., miRNAs [1,2]
As exosomes derived from malignant cells have been shown to modify cells of the tumor microenvironment, we wanted to investigate the potential of melanoma-derived exosomes to reprogram tumor-associated macrophages
We demonstrated by microscopy and flow cytometry that THP-1-derived macrophages are capable of taking up melanoma-derived exosomes (Figure 1C)

Summary

Introduction

Exosomes are small cell-derived membrane nanovesicles of about 50–200 nm in diameter, loaded with proteins, DNA, and coding and non-coding RNAs, e.g., miRNAs [1,2]. They are released in the extracellular environment by living cells and act as carriers for intracellular cell-cell communication [3]. Recent studies show that exosomes released by cancer cells interact amongst others with tumor-infiltrating T cells (TILs) [5], myeloid-derived suppressor cells (MDSCs) or tumor-associated macrophages (TAMs) [6] They induce a phenotypic switch of tumor-infiltrating immune cells and stroma cells, thereby creating a tumor-permissive microenvironment [7,8,9]

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