PT - JOURNAL ARTICLE AU - Ikeda, Yukinori AU - Suehiro, Jun-ichi AU - Oshima, Hiroko AU - Kok, Sau Yee AU - Takahashi, Kazuki AU - Sakurai, Hiroyuki AU - Watabe, Tetsuro AU - Oshima, Masanobu AU - Matsunaga, Yukiko T. TI - Tumor-microvessel on-a-chip reveals sequential intravasation cascade of cancer cell clusters AID - 10.1101/2024.02.28.582606 DP - 2024 Jan 01 TA - bioRxiv PG - 2024.02.28.582606 4099 - http://biorxiv.org/content/early/2024/03/04/2024.02.28.582606.short 4100 - http://biorxiv.org/content/early/2024/03/04/2024.02.28.582606.full AB - 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-β (TGF-β) 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.Competing Interest StatementThe authors have declared no competing interest.