Circulating Tumor Cells Shed Shearosome Extracellular Vesicles in Capillary Bifurcations That Activate Endothelial and Immune Cells.

Circulating tumor cells (CTCs) and their clusters are the cellular drivers of metastasis. This study uses microfluidic models mimicking human capillary bifurcations to better understand how these cells interact with capillary beds. Patient CTCs, CTC-derived explant cells, and numerous cancer cell lines shed nuclei-free fragments in a cell size- and bifurcation-dependent manner. These shedding events, which reduces cell sizes up to 61%, facilitate CTC transit through bifurcations. The shed fragments are a novel subclass of large extracellular vesicles (LEVs) that we name "shearosomes" based on their requirement of shear stress for their biogenesis, and whose proteome is associated with immune-related pathways. Shearosomes exhibit functions that are characteristic of previously identified extracellular vesicles (EVs), including cell-directed internalization by endothelial and immune cells, and intercellular communication capabilities such as disruption of endothelial barrier integrity, polarization of monocytes toward M2 tumor-promoting macrophages, and mediating interactions between endothelial and immune cells. These findings suggest that CTCs shed shearosomes within capillary beds that affect cells implicated in the metastatic cascade.