Brain metastases-derived extracellular vesicles induce binding and aggregation of low-density lipoprotein

Sara Busatto,Panagiotis Z Anastasiadis,Laura Lewis-Tuffin,Jann Sarkaria,Wan-Hsin Lin,Joy Wolfram,Yeshayahu Talmon,Irina Davidovich,Gregory Wurtz,Yubo Yang,Sierra A Walker

doi:10.1186/s12951-020-00722-2

Abstract

BackgroundCancer cell-derived extracellular vesicles (EVs) have previously been shown to contribute to pre-metastatic 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 interactions with circulating components such as low-density lipoprotein (LDL) have been overlooked.ResultsThis 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 presence of LDL accelerates Br-EV uptake by monocytes, which are key components in the brain metastatic niche.ConclusionsCollectively, these data are the first to demonstrate that pro-metastatic EVs display distinct interactions with LDL, which impacts monocyte internalization of EVs.

Highlights

Cancer cell-derived extracellular vesicles (EVs) have previously been shown to contribute to premetastatic niche formation
Corresponding brain metastases (Br)-EVs were obtained from the conditioned medium of a previously characterized brain-topic variant of MDA-MB-231 cells (MDA-MB231-BrM2-831), which was derived from successive implantation, resection, and re-implantation of brainseeking MDA-MB-231 cells in a mouse model (Fig. 1a) [22]
The gene expression profile of the brain-tropic cell line correlates with that of breast cancer brain metastases cells isolated from patients [22], indicating the presence of clinically relevant metastatic features despite being obtained through in vivo selection cycles in an animal model

Summary

Introduction

Cancer cell-derived extracellular vesicles (EVs) have previously been shown to contribute to premetastatic niche formation. 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. EV inter‐ actions with circulating components such as low-density lipoprotein (LDL) have been overlooked. It was shown that cancer cell-derived extracellular vesicles (EVs) contribute to premetastatic niche formation [3, 4]. Minimal focus has been placed on pro-metastatic EV interactions with circulating components, such as low-density lipoprotein (LDL), which has been associated with cancer progression [14,15,16]. LDL is Busatto et al J Nanobiotechnol (2020) 18:162

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Conclusion