Cdc42-Dependent Transfer of mir301 from Breast Cancer-Derived Extracellular Vesicles Regulates the Matrix Modulating Ability of Astrocytes at the Blood–Brain Barrier

Marsha Moses,Towia Libermann,Cassandra Daisy,Hasan Otu,Simon Dillon,Golnaz Morad

doi:10.3390/ijms21113851

Abstract

Breast cancer brain metastasis is a major clinical challenge and is associated with a dismal prognosis. Understanding the mechanisms underlying the early stages of brain metastasis can provide opportunities to develop efficient diagnostics and therapeutics for this significant clinical challenge. We have previously reported that breast cancer-derived extracellular vesicles (EVs) breach the blood–brain barrier (BBB) via transcytosis and can promote brain metastasis. Here, we elucidate the functional consequences of EV transport across the BBB. We demonstrate that brain metastasis-promoting EVs can be internalized by astrocytes and modulate the behavior of these cells to promote extracellular matrix remodeling in vivo. We have identified protein and miRNA signatures in these EVs that can lead to the interaction of EVs with astrocytes and, as such, have the potential to serve as targets for development of diagnostics and therapeutics for early detection and therapeutic intervention in breast cancer brain metastasis.

Highlights

Brain metastasis is a major complication of breast cancer and is associated with an extremely poor prognosis [1,2]
No increase in permeability of brain endothelium to 10 and 70 KDa-dextran was observed following P- or Br-extracellular vesicles (EVs) treatment (Figure 3E) in perfused brain tissues. This observation suggested that the blood–brain barrier (BBB) remained intact during this experiment, supporting the conclusion that the EV-induced decrease in tissue inhibitors of MMPs (TIMPs)-2 was a direct effect of transcytosed Br-EVs on astrocytes. These findings indicate that the transcytosis of Br-EVs and their subsequent uptake by astrocytes can have functional consequences, such as suppressed TIMP-2 expression, that can lead to the preparation of a microenvironment at the BBB suitable for the growth of metastases
We identified a series of mechanisms through which EVs are internalized by, and modulate, the behavior of astrocytes to promote a microenvironment supportive of metastatic growth

Summary

Introduction

Brain metastasis is a major complication of breast cancer and is associated with an extremely poor prognosis [1,2]. Elucidating the early mechanisms of brain metastasis development in breast cancer patients is critical for the development of early diagnostics and effective therapeutics to improve the outcome of this disease. Understanding the role of breast cancer-derived EVs in brain metastasis can provide opportunities for early detection and management of this disease. Our group and others have demonstrated that EVs derived from brain-seeking breast cancer cell lines (Br-EVs) can promote brain metastasis [11,12,13,14]. We focused on astrocytes as one of the major recipients of breast cancer-derived EVs in the brain [11] and sought to elucidate the mechanisms underlying the uptake of breast cancer-derived EVs by these cells and the associated functional consequences

Methods

Results

Conclusion