Prediction of tumor metastasis via extracellular vesicles-treated platelet adhesion on a blood vessel chip.

In preclinical and clinical studies, it has been demonstrated that tumor-educated platelets play a critical role in tumorigenesis, cancer development, and metastasis. Unlike the role of cancer-derived chemokines in platelet activation, the role of cancer-derived extracellular vesicles (EVs) has remained elusive. Here, we found that interleukin-8 (IL-8) in cancer-derived EVs contributed to platelet activation by increasing P-selectin expression and ligand affinity, resulting in increased platelet adhesion on the human vessel-mimicking microfluidic system. Furthermore, platelet adhesion levels on vessels treated with human plasma-derived EVs demonstrated good discrimination between breast cancer patients with metastasis and those without, with the area under the curve (AUC) value of 0.88. While EpCAM expression on EVs could detect the existence of a tumor (AUC = 0.89), it performed poorly in predicting metastasis (AUC = 0.42). We believe that these findings shed light on the role of the interaction between cancer-derived EVs and platelets in pre-metastatic niche formation and tumor metastasis, potentially leading to the development of platelet-tumor interaction-based novel diagnostic and therapeutic strategies.

Recent advances in spheroid-based microfluidic models to mimic the tumour microenvironment.

Three-dimensional (3D) multicellular spheroid models can recapitulate the human tumour microenvironment with more accuracy than conventional cell culture models, as they include complex architectural structures and dynamic cellular interactions. Among the diverse platforms for spheroid formation, microfluidic platforms have been extensively applied to study spheroids because they can mimic the in vivo microenvironment. This review provides an overview of the advantages of 3D spheroid cultures with a summary of the recent applications for tumour microenvironment-focused cellular interactions, as well as the studies on spheroids and external stimuli. These 3D tumour spheroid-based microfluidic devices will provide a platform for a better understanding of cellular and external interactions, as well as the discovery of cancer therapeutics.

Three-Dimensional Human Liver-Chip Emulating Premetastatic Niche Formation by Breast Cancer-Derived Extracellular Vesicles.

The liver is one of the most common sites of breast cancer metastasis and is associated with high lethality. Although the interaction between tumor cells and their microenvironment at metastatic sites has been recognized as a key regulator of tumor progression, the underlying mechanism is not fully elucidated. Here, we describe a three-dimensional (3D) microfluidic human liver-on-a-chip (liver-chip) that emulates the formation of a premetastatic niche to investigate the roles of breast cancer-derived extracellular vesicles (EVs) in liver metastasis. We demonstrate that breast cancer-derived EVs activate liver sinusoidal endothelial cells (LSECs) in the liver-chip, inducing endothelial to mesenchymal transition and destruction of vessel barriers. In addition, we show that transforming growth factor ß1 (TGFß1) in breast cancer-derived EVs upregulates fibronectin, an adhesive extracellular matrix protein, on LSECs, which facilitates the adhesion of breast cancer cells to the liver microenvironment. Furthermore, we observed that EVs isolated from triple-negative breast cancer (TNBC) patients with liver metastasis contain higher TGFß1 levels and induce adhesion of more breast cancer cells to the 3D human liver-chip than do EVs isolated from healthy donors or nonmetastatic TNBC patients. These findings provide a better understanding of the mechanisms through which breast cancer-derived EVs guide secondary metastasis to the liver. Furthermore, the 3D human liver-chip described in this study provides a platform to investigate the mechanisms underlying secondary metastasis to the liver and possible therapeutic strategies.