Abstract 4632: Exosome-mediated transfer of miR-183-5p from tumor cells to macrophages contributes to regulate TAMs phenotypes and promote tumor progression and metastasis

Abstract

Abstract Tumor-associated macrophages (TAMs) perform supportive roles in promoting tumor progression and metastasis. In tumor microenvironment, the phenotypes of TAMs are regulated by a variety of factors, such as cytokines, ligends and products of metabolism. Recently, Exosome-mediated transfer of miRNAs is proved to be a significant way for intercellular communications. Whether exosomal miRNAs derived from tumor cells contribute to TAMs’ phenotypes remains unclear. In this study, we aim to identify the miRNAs in exosomes transferred from tumor cells to macrophages and explore how these miRNAs regulate the TAMs phenotypes. In the beginning we transferred CY3-labled miRNA NC to 4T1 mouse breast cancer cells and then co-cultured with bone marrow-derived macrophages (BMDMs). The CY3 fluorescence could be observed in BMDMs after 48 hour, suggesting that miRNAs could be transferred from tumor cells to macrophages. Next, we performed miRNAs sequencing in either BMDM or exosomes derived from 4T1 cancer cells. We analyzed and compared the miRNAseq data by bio- informatics and found that there were 30 of the most abundant miRNAs in 4T1 exosomes, and nearly all of which were rich in BMDMs. However, it was found interestingly that miR-183-5p was extremely low in BMDMs. Furthermore, we treated BMDMs with exosomes isolated form 4T1 cell conditioned medium, and then we found importantly the miR-183-5p in BMDMs was increased significantly, while cultured with exosome-depleted 4T1 conditioned medium, the expression of miR-183-5p in BMDMs was not changed. Meanwhile, we isolated TAMs from 4T1 mouse breast tumor while spleen macrophages from normal mouse as a control. The expression of miR-183-5p in TAMs was much higher than that in spleen macrophages. Moreover, it was determined that expression of pro-inflammatory cytokine TNF and IL-6 in BMDM were increased significantly in BMDMs treated with 4T1-derived exosomes. Correspondingly, transferred miR-183-5p mimic into BMDMs, the expression of TNF and IL-6 were also increased. Finally we co-cultured 4T1 cells with BMDMs transferred with miR-183-5p, and the migration and invasion of 4T1 cells were significantly enhanced. Taken together, our study demonstrate that miR-183-5p that high expression in 4T1 exosomes can transferred into macrophages to regulated their phenotypes and promote tumor progression and metastasis in breast tumor microenvironment. Citation Format: Jian Guo, Wei Wang, Yan Liu, Huiwen He, Chen Zhang, Chong Chen, Yunping Luo. Exosome-mediated transfer of miR-183-5p from tumor cells to macrophages contributes to regulate TAMs phenotypes and promote tumor progression and metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4632. doi:10.1158/1538-7445.AM2017-4632