Abstract 2190: Brain-seeking extracellular vesicles derived from metastatic breast cancer cells modulate brain endothelial cell metabolism

Abstract

Abstract Breast cancer, particularly the triple-negative subtype, is the primary cause of brain metastasis in women and affects ~10-16% of breast cancer patients. Breast cancer patients diagnosed with brain metastasis have limited therapeutic options and, therefore, a dismal prognosis with a median survival time of ~10 months. Recent studies have suggested that metastatic cells extravasate and grow along the blood-brain barrier (BBB) in a favorable microenvironment called the pre-metastatic niche. However, the early steps leading to the onset of breast-to-brain metastasis are poorly understood, limiting the development of strategies to prevent, detect and treat premetastatic or early-stage lesions. It is now well accepted that extracellular vesicles (EVs), nanoparticles secreted from cancer cells, can travel to distant organs, activate resident cells and promote the remodeling of the extracellular matrix and significantly impact organ-specific metastatic spread. Using our mouse model of breast to brain metastasis, we have demonstrated, for the first time, that EVs derived from brain-seeking breast cancer cells (Br-EVs) breach the intact BBB via transcytosis, are taken up by astrocytes and cause a significantly increased incidence of brain metastasis. Within this context, we are studying the interactions between Br-EVs and brain endothelial cells (ECs), the latter being a key functional component of the BBB. Utilizing primary human ECs and using a transwell assay established in our laboratory as an in vitro model of the BBB, we have identified the mechanism(s) through which Br-EVs modulate EC endocytic metabolism in favor of increased vesicle recycling and transcytosis. Our mechanistic studies demonstrate that ECs treated with Br-EVs show a significant decrease of multiple target proteins, all of which are involved in the long-recycling loop of the endocytic vesicles. Br-EVs mediate, at least in part, their effect through the delivery to the target cells of a specific subset of micro RNAs. As a result, Br-EVs upregulate EC basal transcytosis rate promoting their transfer to the brain parenchyma. These findings indicate that Br-EVs can alter BBB basal metabolism and help to prepare a microenvironment, better known as the pre-metastatic niche, that promotes and sustains the survival and growth of breast cancer metastases in the otherwise hostile brain microenvironment. These results increase our understanding of the early events that facilitate breast-to-brain metastasis and have the potential to identify key regulators in the early steps of brain metastasis formation. Our mechanistic studies will also inform and contribute to the development of EV-based diagnostic and therapeutic strategies for the early management of breast cancer patients with brain metastasis. (This work was supported by NIH R21 CA253051-01 and the Breast Cancer Research Foundation). Citation Format: Sara Busatto, Golnaz Morad, Marsha Moses. Brain-seeking extracellular vesicles derived from metastatic breast cancer cells modulate brain endothelial cell metabolism [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2190.