Microphysiological Systems to Study Metastasis at High Spatiotemporal Resolution

Shirure, Venktesh ;   Waterman, Marian ;   George, Steven

Metastasis, the most devastating consequence of cancer, remains challenging to treat, and better understanding of the metastatic process is required to devise improved treatments. Animal models have improved our understanding of these processes, but they provide limited spatial and temporal resolution of cellular events. In this study, we designed a microfluidic platform that supports growth of tumor spheroids that are spatially separated from vascular networks that are perfusable and provide precise control over interstitial flow. We cultured colon cancer tumor spheroids to study the role of Wnt signaling – the oncogenic driver of colon carcinogenesis in angiogenesis. We show that the angiogenic sprouting of vessels is biased towards a positive concentration gradient of the tumor secreted morphogens, such as VEGF. To study angiogenesis in response to Wnt signaling, wild type or dnTCF-1 (with reduced level of Wnt signaling) SW620 colon cancer tumors were grown in the vicinity of endothelial vasculature. The vasculature was characterized for multiple endpoints including total vessel length, sprouting, and vascular branching. The results of the experiments indicate that high Wnt signaling affects tumor associated vasculature. Therefore, such microphysiological systems mimicking features of tumor tissues may allow us to further decipher the metastatic cascade.