Vrynas Angelos, Bazban-Shotorbani Salime, Arfan Sara, Satia Karishma, Cunningham Brian, Sagindykova Gauhar, Ashna Mymuna, Zhang Aoyu, Visan Diana, Chen Aisher, Matthews-Palmer Teige, Carter Mathew, Blackhall Fiona, Simpson Kathryn L, Dive Caroline, Huang Paul, Au Sam H
Department of Bioengineering, Imperial College London, London, SW7 2AZ, United Kingdom.
Division of Cancer Biology, The Institute of Cancer Research, London, SM2 5NG, United Kingdom.
Adv Sci (Weinh). 2025 Jun 9:e06339. doi: 10.1002/advs.202506339.
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.
循环肿瘤细胞（CTCs）及其聚集体是转移的细胞驱动因素。本研究使用模拟人体毛细血管分支的微流控模型，以更好地了解这些细胞如何与毛细血管床相互作用。患者的循环肿瘤细胞、源自循环肿瘤细胞的外植体细胞以及众多癌细胞系以细胞大小和分支依赖的方式脱落无核碎片。这些脱落事件使细胞大小减小达61%，促进了循环肿瘤细胞通过分支。脱落的碎片是一种新型的大细胞外囊泡（LEVs）亚类，我们基于其生物发生对剪切应力的需求将其命名为“剪切体”，其蛋白质组与免疫相关途径有关。剪切体表现出先前鉴定的细胞外囊泡（EVs）的特征性功能，包括内皮细胞和免疫细胞介导的细胞定向内化，以及细胞间通讯能力，如破坏内皮屏障完整性、使单核细胞向促进肿瘤的M2巨噬细胞极化，以及介导内皮细胞和免疫细胞之间的相互作用。这些发现表明，循环肿瘤细胞在毛细血管床内脱落剪切体，影响参与转移级联反应的细胞。
