Melanoma‐derived extracellular vesicles instigate proinflammatory signaling in the metastatic microenvironment

Abstract

The major cause of melanoma mortality is metastasis to distant organs, including lungs and brain. Reciprocal interactions of metastasizing tumor cells with stromal cells in secondary sites play a critical role in all stages of tumorigenesis and metastasis. Changes in the metastatic microenvironment were shown to precede clinically relevant metastases, and may occur prior to the arrival of disseminated tumor cells to the distant organ, thus creating a hospitable “premetastatic niche.” Exosomes secreted by tumor cells were demonstrated to play an important role in the preparation of a hospitable metastatic niche. However, the functional role of melanoma‐derived exosomes on metastatic niche formation, and the downstream pathways activated in stromal cells at the metastatic niche are largely unresolved. Here we show that extracellular vesicles (EVs) secreted by metastatic melanoma cells that spontaneously metastasize to lungs and to brain, activate proinflammatory signaling in lung fibroblasts and in astrocytes. Interestingly, unlike paracrine signaling by melanoma cells, EVs secreted by metastatic melanoma cells instigated a proinflammatory gene signature in lung fibroblasts but did not activate wound‐healing functions, suggesting that tumor cell‐secreted EVs activate distinct CAF characteristics and tumor‐promoting functions. Moreover, melanoma‐secreted EVs also activated proinflammatory signaling in astrocytes, indicating that EV‐mediated reprogramming of stromal cells is a general mechanism of modulating the metastatic niche in multiple distant organs. Thus, our study demonstrates that melanoma‐derived EVs reprogram tumor‐promoting functions in stromal cells in a distinct manner, implicating a central role for tumor‐derived EV signaling in promoting the formation of an inflammatory metastatic niche.

The Role of Cancer-Associated Fibroblasts and Extracellular Vesicles in Tumorigenesis

“…Several studies demonstrate roles in tumorigenesis for other EV cargo types, including mRNA and lncRNA. Indeed, melanoma cell-derived EVs exhibited differential expression of over 1600 transcripts when compared to fibroblast-derived EVs, suggesting an important role for mRNA incorporation into EVs [138]. Specific mRNAs, including those encoding TNF-α, TGF-β, and IL-6, have been found to be transferred from cancer cells to fibroblasts and to regulate fibroblast differentiation and function [130].…”

“…As a result, the activated fibroblasts secrete pro-inflammatory cytokines and promote metastatic cancer growth [172]. Furthermore, EVs secreted by metastatic melanoma cells induce a pro-inflammatory profile in lung fibroblasts without any differences in wound healing functions, while also triggering pro-inflammatory signaling in astrocytes [138].…”

Extracellular Vesicles in Cancer Metastasis: Potential as Therapeutic Targets and Materials

“…Cancer cells educate fibroblasts through EVs, which leads to the progression of metastasis [ 48 ]. Cancer-derived EVs are involved in the reprogramming of normal stromal fibroblasts into activated cancer-associated fibroblasts (CAFs) in chronic lymphocytic leukemia [ 49 ], hepatocellular carcinoma (HCC) [ 50 ], and melanoma [ 51 ]. These studies revealed that the CAF transition leads to metastatic niche formation and promotes cancer metastasis.…”

The Function of Astrocyte Mediated Extracellular Vesicles in Central Nervous System Diseases

“…For example, astrocytes-derived exosomes enriched with miR-19a may increase brain cancer metastasis by increasing the loss of phosphatase and tensin homolog (PTEN) in tumor cells and C-C motif chemokine ligand 2 (CCL2) chemokine secretion ( Zhang et al, 2015 ). Melanoma cells secrete EVs which can activate pro-inflammatory signals in astrocytes and promote metastasis and tumor formation ( Gener Lahav et al, 2019 ). Glioma-derived EVs increase inhibition of TP53 and MYC signaling pathway activation in astrocytes.…”