Abstract 2667: Platelet microparticles infiltrating solid tumors transfer miRNAs and modulate tumor angiogenesis and growth

Abstract Platelet-derived microparticles are associated with enhancement of metastasis and poor cancer outcomes. Platelet microparticles can transfer platelet microRNAs (miRNAs) to vascular cells upon co-incubation in vitro, but the contributions of platelet microparticles and miRNAs to tumor progression are still poorly understood. Tumor vasculature is highly permeable, allowing the possibility of platelet microparticle-tumor cell interaction in primary solid tumors. Here we show that platelet microparticles infiltrate solid tumors in humans and mice, attach to tumor cells, and transfer platelet-derived RNA, including miRNAs, to tumor cells in vivo as well as in vitro. MiR-24 was a major species in this transfer. We identified RNA targets of platelet-derived miR-24 in lung carcinoma cells, which included mt-Nd2, a mitochondrial mRNA which lacks a 3’-UTR, and Snora75, a non-coding small nucleolar RNA. These RNAs were depleted in platelet microparticle-treated tumor cells, resulting in mitochondrial dysfunction and tumor cell growth inhibition, in a miR-24-dependent manner. Blockade of miR-24 in tumor cells accelerated tumor growth in vivo, and prevented tumor growth inhibition by platelet microparticle transfusion. Thus, platelet microparticles inhibit lung carcinoma cell proliferation and solid tumor growth via transfer of miR-24. However, global depletion of platelet miRNAs by platelet-specific deletion of Dicer1 inhibited tumor angiogenesis, platelet microparticle infiltration, and delayed tumor growth in mice. Thus, platelet-derived miRNAs transfer in vivo to tumor cells in solid tumors via microparticles, regulate tumor cell gene expression, and modulate tumor progression, whereas platelet miRNAs promote tumor angiogenesis. These findings shed novel insight onto mechanisms of horizontal gene transfer and add multiple layers to the regulatory roles of miRNAs and platelet microparticles in tumor progression. Citation Format: James V. Michael, Jeremy G.T. Wurtzel, Guang Fen Mao, A. Koneti Rao, Nicholas E. Hoffman, Sudarsan Rajan, Muniswamy Madesh, Fabian Jana, Marvin Nieman, Jesse W. Rowley, Andrew S. Weyrich, Lawrence E. Goldfinger. Platelet microparticles infiltrating solid tumors transfer miRNAs and modulate tumor angiogenesis and growth. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2667.