Brain metastases-derived extracellular vesicles induce binding and aggregation of low-density lipoprotein
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Journal of Nanobiotechnology Open Access
RESEARCH
Brain metastases‑derived extracellular vesicles induce binding and aggregation of low‑density lipoprotein Sara Busatto1,2,3* , Yubo Yang1, Sierra A. Walker1, Irina Davidovich5, Wan‑Hsin Lin4, Laura Lewis‑Tuffin4, Panagiotis Z. Anastasiadis4, Jann Sarkaria6, Yeshayahu Talmon5, Gregory Wurtz7 and Joy Wolfram1*
Abstract Background: Cancer cell-derived extracellular vesicles (EVs) have previously been shown to contribute to premetastatic niche formation. Specifically, aggressive tumors secrete pro-metastatic EVs that travel in the circulation to distant organs to modulate the microenvironment for future metastatic spread. Previous studies have focused on the interface between pro-metastatic EVs and epithelial/endothelial cells in the pre-metastatic niche. However, EV inter‑ actions with circulating components such as low-density lipoprotein (LDL) have been overlooked. Results: This study demonstrates that EVs derived from brain metastases cells (Br-EVs) and corresponding regular cancer cells (Reg-EVs) display different interactions with LDL. Specifically, Br-EVs trigger LDL aggregation, and the pres‑ ence of LDL accelerates Br-EV uptake by monocytes, which are key components in the brain metastatic niche. Conclusions: Collectively, these data are the first to demonstrate that pro-metastatic EVs display distinct interactions with LDL, which impacts monocyte internalization of EVs. Keywords: Extracellular vesicles, Lipoproteins, Brain metastasis, Macrophages, Pre-metastatic niche Background Metastasis accounts for up to 90% of all cancer-related deaths [1, 2]. However, many aspects of the metastatic process are poorly understood, limiting the development of diagnostic and therapeutic strategies to prevent metastatic spread. Recently, it was shown that cancer cell-derived extracellular vesicles (EVs) contribute to premetastatic niche formation [3, 4]. EVs are cell-secreted nanoparticles surrounded by a lipid bilayer enclosing bioactive cargo (proteins, carbohydrates, lipids, and nucleic acids) involved in cell communication in both physiological and pathological conditions [5–8]. Aggressive *Correspondence: [email protected]; wolfram.joy@mayo. edu 1 Department of Biochemistry and Molecular Biology, Department of Physiology and Biomedical Engineering, Department of Transplantation, Mayo Clinic, Jacksonville, FL 32224, USA Full list of author information is available at the end of the article
primary tumors have been found to secrete pro-metastatic EVs that travel within the circulation to distant organs, causing modulation of the microenvironment for future metastatic spread [3, 4]. Animal studies have demonstrated that pretreatment with pro-metastatic EVs prior to cancer cell injection can substantially increase the formation of subsequent metastatic lesions [4, 9, 10]. Evidence suggests that EV-mediated metastatic organotropism involves integrin interactions with tissue-specific epithelial, endothelial, or resident immune cells [4, 11]. Cancer cel
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