Kok, S. Y. | Search bioRxiv

bioRxiv2024

Tumor-microvessel on-a-chip reveals sequential intravasation cascade of cancer cell clusters

Circulating tumor cell (CTC) clusters are often detected in blood samples of patients with high-grade tumor and are associated with tumor metastasis and poor prognosis. However, the underlying mechanisms by which CTC clusters are released from primary tumors beyond blood vessel barriers remain unclear. In this study, a three-dimensional (3D) in vitro culture system is developed to visualize tumor intravasation by positioning tumor organoids with distinct genetic backgrounds to surround microvessels. We visualized tumor intravasation in a cluster unit, including collective migration in the collagen gel, vessel co-option, and the release of CTC clusters as one of cluster invasion manners yet reported previously. In addition, our results show that both transforming growth factor-{beta} (TGF-{beta}) expression in tumor cells and subsequent induction of activin expression in endothelium are essential for tumor cell intravasation accompanied with endothelial-to-mesenchymal transition (EndoMT) in microvessels. Our 3D in vitro system can be used to develop therapeutic strategies for tumor metastasis by targeting CTC clusters.

cancer biology↗

bioRxiv2024

Spatiotemporal observation reveals metastatic tumor-driven vascular remodeling as a potential route to polyclonal colonization

Polyclonal metastasis, which arises from clusters of circulating tumor cells, promotes metastasis development and has become a major target of metastasis inhibition. Mouse experiments have clearly verified that nonmetastatic and metastatic tumors coexist and form metastatic nests, but the detailed mechanism of extravasation remains unclear. We established a three-dimensional tumor microvessel model to investigate extravasation between nonmetastatic tumors, metastatic tumors, and mosaic tumor organoids in a mixed state by time-lapse imaging and to determine the sequential steps of the extravasation of tumor cells via vascular remodeling. This comparison revealed a new concept of extravascular invasion via vascular remodeling in metastatic carcinoma. Furthermore, the involvement of liver host cells, the hepatic stellate cells, demonstrated an interaction with metastatic cells to facilitate metastatic foci formation. Moreover, Adam28 was highly expressed exclusively in metastatic tumor cells, suggesting its involvement in vascular remodeling. These results demonstrate the ability of metastatic tumor cells for extravasation in polyclonal metastasis, which may lead to the development of new therapeutic targets.

cancer biology↗