(549f) 3D Organotypic Cancer Model: Revealing Vascular Ablation during Pancreatic Cancer Invasion

Although the diagnosis and treatment of cancer in its earliest stages have significantly improved outcomes in many tumors, survival rates in patients with tumors that have spread to distant sites remain dismal. As a result, the vast majority of cancer mortalities stem from metastasis and its complications. Metastasis describes the process where tumor cells escape from the tumor primary sites to enter the blood stream, and arrive at other distant organs to form secondary tumors. Among metastatic cancers, pancreatic ductal adenocarcinoma (PDAC) has remained one of the deadliest metastatic diseases over the past decades owing to the high incidence of metastasis of tumor cells. Notably, patients with PDAC exhibit a high degree of vascular invasion and abundant circulating tumor cells in the bloodstream, which suggest that PDAC cells are highly efficient to gain access to the blood stream. Genetically engineered mouse models for PDAC have made many progresses to understand the tumor biology of PDAC during tumor progression and development. Despite this, the interactions between PDAC cells and blood vessels remain poorly understood, partly due to the lack of in vitro models to enable close examination of tumor cells and endothelial cells at the blood vessel interface.

Here, we describe an organotypic PDAC-on-a-chip culture model to examine vascular invasion in PDAC. The model features two hollow cylindrical channels embedded within a three-dimensional matrix [1]. One of the channels was lined with endothelial cells to mimic blood vessel while the other was seeded with PDAC cells to mimic a tumorous pancreatic duct [2]. In this model, PDAC cells from the tumorous pancreatic duct invaded through the intervening matrix and into the blood vessel lumen, induced endothelial cell apoptosis, and ultimately ablated the endothelial cells. A phenomenon we termed vascular ablation. We later confirmed the observation of vascular ablation by tumor cells in our organotypic model by using in vivo model of ectopic PDAC growth and genetically engineered mouse model of PDAC. Interestingly, PDAC human patients have also exhibited vascular invasion and tumor-like cells, which populate the lumen side of the blood vessels in previous reports. This confirms the clinically relevant observation of vascular ablation in our 3D organotypic model. Additionally, using small molecule inhibitors and CRISPR technology, we identified the Activin-ALK7 pathway as a critical mediator of vascular ablation by PDAC. This tumor-on-a-chip model thus provides an important in vitro platform to reveal previously unappreciated mechanisms by which tumors interact with tumor blood vessels and enable identification of signaling pathway to target tumor invasion and vascular ablation in PDAC.

[1] Nguyen, D.H., Stapleton, S.C., Yang, M.T., Cha, S.S., Choi, C.K., Galie, P.A., Chen, C.S. (2013). Biomimetic model to reconstitute angiogenic sprouting morphogenesis in vitro. Proceedings of the National Academy of Sciences. 110(17): 6712-6717.

[2] Nguyen, D.H., Esak, L., Alimperti, S., Norgard. R.J., Wong, A., Lee, J.J.K., Eyckmans, J., Stanger, B.Z., Chen, C.S. (2019). A biomimetic pancreatic cancer on-chip reveals endothelial ablation via ALK7 signaling. Science Advances. 5(8): eaav6789