Abstract 2743: Mesothelioma exosomes as potential new cancer therapy
Authors: Munson Phillip B. , Hall Elizabeth M. , Shukla Arti 
Published: August 2019

Abstract
Malignant mesothelioma (MM) is a highly invasive cancer arising on the mesothelial surface of organ cavities, predominantly the pleura, and is a direct result of asbestos exposure. Once diagnosed, the disease is virtually incurable with a median lifespan of 6-12 months. Additionally, there is no means of early diagnosis prior to disease symptoms, and the standard of care chemotherapeutics do not extend the life of patients. Taken together, 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). Exosomes are vesicles secreted from every known mammalian cell type and present in essentially all body fluids. Most notably, exosomes play an outsize role in cancer biology. We initially sought to uncover the exosomal miRNAs secreted from MM tumor cells and found a unique signature associated with MM cancer exosomes compared to their mesothelial cell counterparts. The surprising discovery, however, was that the most abundant miRNAs in MM cancer exosomes were tumor suppressors, particularly the pro-apoptotic miR-16-5p. This led us to hypothesize that MM preferentially secreted tumor-suppressor miRNAs via exosomes in order to avoid their effect of killing the tumor cells. Through three novel avenues of potential therapeutic advance, coupled with the possibility of using these exosomal miRNAs as future biomarkers, we have embarked on an innovative strategy to kill MM tumor cells. We have employed small molecule inhibitors to block exosome secretion, thereby reducing miR-16 exosome loss and rebuilding the cellular miR-16 leading to cell death, decreased migration/invasion, and loss of miR-16 target oncogenic proteins CCND1 and BCL2. In addition, we have force-fed concentrated MM tumor exosomes back to MM tumor cells, which led to remarkable levels of cell death, and a reduction in the same oncogenes, CCND1 and BCL2 as seen in our exosome inhibition trials. We have recapitulated these results with direct transfection of miR-16, leading to very comprehensive and convincing evidence that MM tumor cells do in fact secrete high levels of miR-16, and that when re-delivered back to the producer tumor cells through exosome inhibition, exosome force-feeding, or direct transfection, leads to cancer cell death and loss of oncogenic proteins CCND1 and BCL2. Our data, thus far, provide striking new information on a tumorigenic mechanism of MM tumor cells by preferential miR-16 secretion. Moreover we indicate possible miRNA biomarkers through exosomes, and show a never before proposed approach to targeting the death of MM cancer cells by blocking exosome secretion or force-feeding back their own exosomes. This study is supported majorly by Department of Defense, UVM REACH, the UVM Department of Pathology Fellowship, and in small part by NIH RO1.
Citation Format: Phillip B. Munson, Elizabeth M. Hall, Arti Shukla. Mesothelioma exosomes as potential new cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2743.