Abstract

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The future of cancer therapy relies on robust drug combinations. Traditional screening for drug discovery uses 2D monocultures. However, recent studies have shown that 3D cultures provide a more physiological platform to study cancer. Unfortunately, these systems do not capture interactions between tumor cells and the angiogenic component. The goal of this work is to establish a 3D in vitro co-culture system combining these components to create a high-throughput model to study cell interactions and screen anti-angiogenic and anti-tumorigenic therapies. Human endothelial cells were allowed to undergo tubulogenesis in a matrigel matrix to which metastatic breast cancer MDA-MB-231 cells were added. Interestingly, instead of forming embryoid bodies, the MDA cells align and incorporate into the endothelial vessels. Using this model system, we elucidate FAK and β1 integrin as mediators of the cell interactions. RNAi inhibition of FAK and β1 integrin resulted in the disruption of the architecture with 3.4 (p<0.001) and 8.6 (p<0.001) fold change in cell interactions, respectively. To probe downstream mediators of the FAK-β1 signaling pathway, small molecule inhibitors were used to perturb this architecture, resulting in a 68% (p<0.05) decrease in invasive capacity. In conclusion, our studies show that a 3D co-culture system provides a powerful platform for screening combination therapies.

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Supported by DoD BCRP.

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