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Yuting Liu,1,* Jie Tang,1,* Xiaolan Qiu,1,* Lucy A Teng,2 Mukesh K Sriwastva,2 Xuedong Han,1 Zhi Li,1 Minmin Liu,1 Shuangyue Liu,1 Dongzhu Da,1 Zhi Li,1 Linlin Zhen,1 Yi Ren1 1Department of Breast and Thyroid Surgery, The Affiliated Huaian No.1 People’s Hospital of Nanjing Medical University, Huai’an, Jiangsu, People’s Republic of China; 2Brown Cancer Center, Department of Microbiology & Immunology, University of Louisville, Louisville, KY, USA*These authors contributed equally to this workCorrespondence: Yi Ren; Linlin Zhen, Department of Breast and Thyroid Surgery, The Affiliated Huai’an No. 1 People’s Hospital, Nanjing Medical University, Huai’an, Jiangsu, People’s Republic of China, Email only_renyi@163.com; simu1027@sina.comBackground: Recent therapeutic approaches have improved survival rate for women with breast cancer, but the survival rate for metastatic breast cancer is still low. Exosomes released by various cells are involved in all steps of breast cancer development.Methods: We established the multimodal imaging report expression in breast cancer cells with lentivirus vectors pGluc and pBirA to investigate the secreted exosomes. Comparative microRNA (miRNA) analysis was performed with miRNA qPCR array in mice with breast cancer lung metastasis. The co-immunoprecipitation and chromatin immunoprecipitation assays were used to identify the mechanism of miRNA sorting to exosomes. The potential therapeutic strategy using an anti-sorting antibody was used to investigate breast cancer lung metastasis.Results: We identified 26 high- and 32 low-expression level miRNAs in exosomes from metastasis compared to those from primary tumors and normal tissues. The tumor suppressors, including miR-200c and let-7a, were reduced in tumor tissues and metastasis but increased in the respective exosomes compared to normal tissues. Furthermore, the Ras-related protein (Rab1A) facilitated miR-200c sorting to exosomes circumventing the influence of tumor suppressor miR-200c on tumor cells, while the metastatic exosome cargo miR-200c inhibited F4/80+ macrophage immune response. Administration of anti-Rab1A antibody significantly repressed the trafficking of miR-200c to exosomes and breast cancer lung metastasis.Conclusion: Our study has identified a novel molecular mechanism for breast cancer lung metastasis mediated by exosome cargo miRNAs and provided a new therapeutic strategy for cancer immunotherapy.Graphical Abstract: Keywords: extracellular vehicles, exosomes, breast cancer lung metastasis, miR-200c, Rab1A, miRNA sorting |
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