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Abstract
Malignant mesothelioma (MM) is an asbestos-induced cancer arising on the mesothelial surface of organ cavities. MM is essentially incurable without a means of early diagnosis and no successful standard of care. These facts indicate a deep chasm of knowledge that needs to be filled. Our group recently delved into MM tumor biology from the perspective of exosome-contained microRNAs (miRNAs). We discovered that the most abundant miRNAs in MM cancer exosomes were tumor suppressors, particularly miR-16-5p. This observation lead us to hypothesize that MM cells preferentially secreted tumor-suppressor miRNAs via exosomes. Through separate avenues of potential therapeutic advance, we embarked on an innovative strategy to kill MM tumor cells. We employed small molecule inhibitors to block exosome secretion, thereby reducing miR-16-5p exosome loss and replenishing cellular miR-16-5p leading to reduced tumorigenic capacity and miR-16-5p target oncoproteins CCND1 and BCL2. Additionally, we force-fed MM tumor exosomes back to MM tumor cells, which led to cell death, and a reduction in the same oncoproteins. We recapitulated these results with direct transfection of miR-16-5p, confirmed that this is a cancer-cell specific effect, and elucidated a part of the miR-16-5p mechanism of exosome loading.
Highlights
Malignant mesothelioma (MM) is an asbestos-induced cancer arising on the mesothelial surface of organ cavities
The isolation of exosome samples was characterized by transmission electron microscopy (TEM), Western blot analysis for exosomal marker CD81, and nanoparticle tracking analysis (NTA) (Supplementary Fig. 1)
Mesothelioma cancer cells secrete high levels of miR-16-5p in exosomes. miRNA microarray profiling was conducted on isolated exosomal RNA from MM cell lines and primary mesothelial cells to compare non-cancer versus cancer signature (Fig. 1A)
Summary
Malignant mesothelioma (MM) is an asbestos-induced cancer arising on the mesothelial surface of organ cavities. As a new piece to the puzzle of cancer, exosomes represent an important aspect of biological signaling between cells and as a means of novel biomarker identification strategies[4]. This is directly linked to the biofunctional cargo enriched in exosomes such as proteins, miRNAs, and lipids[5,6]. MicroRNAs (miRNAs) have been implicated in oncogenesis and could be exploited as potential therapeutic targets[11].There have been multiple of investigations into the miRNAs involved in mesothelioma, by Glen Reid’s group who has summarized a large swath of such knowledge and reported miRNA levels in MM tumor cells and tissues. Been proposed[14] Notably, as per our knowledge only one current research article looks at the miRNA signature associated with circulating extracellular vesicle (EV) miRNAs in MM patients, and found that miR-103a-3p and miR-30e-3p were discriminatory for MM from asbestos-exposed patients with no cancer[15]
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