| Prostate cancer is the most common non-skin cancer in United States men. Despite recent advances, mortality still remains high due to the emergence of therapy-resistant cancer cells that metastasize. Recently it has been postulated that only cancer stem cells (CSCs) are able to establish metastases, and therefore are the essential targets to destroy. Unfortunately, current use of CSCs is limited by the small number of CSCs that can be isolated, and the difficulty of culturing the CSCs in vitro. Furthermore, current in vitro-based metastatic prostate cancer models do not faithfully recreate the complex multi-cellular, three-dimensional (3D) tumor microenvironment seen in vivo. It is therefore crucial to develop effective in vitro prostate cancer culture and testing systems that mimic the actual in vivo tumor niche microenvironment. Here we utilized novel microscale technologies to develop an accurate 3D metastatic tumor model for detailed study of metastatic prostate cancer dormancy as well as accurate anti-cancer therapeutics screening and testing in vitro. Guided by the observation that prostate cancer cells parasitize and stay quiescent in the hematopoietic stem cell niche that is rich in osteoblasts and endothelial cells in vivo, a microfluidic device was established to create 3D spheroid culture of prostate cancer cells supported by osteoblasts and endothelial cells. This 3D metastatic prostate cancer model recapitulates the physiologic, dormant growth behavior of prostate cancer cells in the hematopoietic stem cell niche. Furthermore, we developed a hanging drop-based high-throughput platform for general formation, stable long-term culture, and robust drug testing and screening of 3D spheroids. Using this platform, we found significant differences in drug sensitivities against cells cultured under conventional 2D conditions versus physiological 3D models. A variety of techniques and methods were also established to specifically pattern the spatial localization of different co-culture cell types within a spheroid in this platform for accurate engineering of the 3D metastatic prostate cancer niche microenvironment. Collectively, these biological findings and technological innovations have led to advances in the understanding of prostate cancer biology and progress towards development of novel tools and therapeutics to fight against tumorigenic cancer cells. |
