Cancer Exosomes Perform Cell-Independent MicroRNA Biogenesis and Promote Tumorigenesis

Authors and Affiliations:

Sonia A. Melo^{1, 2}, Hikaru Sugimoto^{1, 2}, Joyce T. O’Connell², Noritoshi Kato², Alberto Villanueva³, August Vidal⁴, Le Qiu⁵, Edward Vitkin⁵, Lev T. Perelman⁵, Carlos A. Melo^{6, 7}, Anthony Lucci⁸, Cristina Ivan⁹, George A. Calin¹⁰, Raghu Kalluri^{1, 2,}

¹ Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA

² Division of Matrix Biology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA

³ Translational Research Laboratory, Catalan Institute of Oncology, Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, Barcelona 08908, Spain

⁴ Department of Pathology, Hospital Universitari de Bellvitge, Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, Barcelona 08908, Spain

⁵ Department of Obstetrics, Gynecology, and Reproductive Biology, and Department of Medicine, Center for Advanced Biomedical Imaging and Photonics, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA

⁶ Division of Gene Regulation, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands

⁷ Doctoral Programme in Biomedicine and Experimental Biology, Centre for Neuroscience and Cell Biology, 3004-517 Coimbra, Portugal

⁸ Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA

⁹ Center for RNA Interference and Non-coding RNAs, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA

¹⁰ Department of Experimental Therapeutics, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA

Abstract:

Exosomes are secreted by all cell types and contain proteins and nucleic acids. Here, we report that breast cancer associated exosomes contain microRNAs (miRNAs) associated with the RISC-Loading Complex (RLC) and display cell-independent capacity to process precursor microRNAs (pre-miRNAs) into mature miRNAs. Pre-miRNAs, along with Dicer, AGO2, and TRBP, are present in exosomes of cancer cells. CD43 mediates the accumulation of Dicer specifically in cancer exosomes. Cancer exosomes mediate an efficient and rapid silencing of mRNAs to reprogram the target cell transcriptome. Exosomes derived from cells and sera of patients with breast cancer instigate nontumorigenic epithelial cells to form tumors in a Dicer-dependent manner. These findings offer opportunities for the development of exosomes based biomarkers and therapies.

Journal: Cancer Cell

Link: http://dx.doi.org/10.1016/j.ccell.2014.09.005