Overview

Pancreatic ductal adenocarcinoma (PDAC), the most common pancreatic cancer subtype, is among the deadliest solid malignancies with a five-year survival rate of less than 10%. Due to the high unmet medical need, the development of novel, ideally targeted therapies are urgently needed.

Introduction

Classically, drug screenings are performed on plate cultured pancreatic tumor cells. However, such 2D-models showed limited translational relevance as they fail to recapitulate the cellular heterogeneity, structural complexity and vascularization of PDAC tumors. Screening drugs in complex 3-D models of PDAC might help to better predict patient outcome.

Methods

The novel Dynamic42 bio-chip is comprised of three independent chambers separated by porous membranes. The top chamber reflects the pancreatic vasculature with an endothelial cell lining under continuous perfusion. In the underlying middle chamber PDAC-spheroids, composed of tumor and pancreatic stellate cells, are cultured in porous microcavities. The bottom chamber is perfused to support growth of spheroids and allow sampling of spheroid-conditioned media.

Results

PDAC spheroids and endothelial cells can be independently cultured in this system. Co-culture of spheroids and vasculature results in a loss of endothelial barrier integrity, mimicking vascular leakage also observed in vivo. Barrier integrity can be restored by introducing an additional layer of tumor-derived pancreatic stellate cells in the middle chamber.

Conclusion

The presented microfluidic system recapitulates 3D tissue organization of PDAC. It models two key features of the tumor, the interaction of tumor cells with the microenvironment, and the linkage of the tumor to a vasculature. The system now enables researchers to in vitro screen vascular application of novel PDAC drug candidates.