Our understanding of the biological mechanisms that regulate cancer metastasis are poorly understood, in part, because of the lack of relevant and high-throughput assay systems that allow for the efficient study of the myriad of parameters involved. These parameters include not just the cancer cells, but the microenvironment the cancer cells encounter at various steps in the metastatic cascade. For example, in order to metastasize, cancer cells must leave the primary tumor and navigate the circulatory system via intravasation and extravasation (into and out of blood vessels). This occurs amidst a complex environment consisting of different interacting cell types that likely effect and regulate invasion/intravasation and extravasation/colonization. Here we propose to develop an in vitro high throughput model of intravasation and extravasation that incorporates several essential structure/function relationships found in vivo. Further, we will validate the in vitro assay with a in vivo mouse model and a microarray of human tissue samples from primary and metastatic mammary tumors. We will use novel micro fabrication methods (e.g. viscous fingering) to create high-throughput arrays of micro vessels (e.g. endothelial lined lumens created within extracellular matrix). The assay platform integrates microfluidics and multiple cell type 3D culture to provide an automated system for identifying the effectors of intravasation and extravasation - two key steps in the metastatic cascade. Finally, we will apply the assay platform to perform a discovery-based screen of the microenvironmental factors suspected to influence breast cancer metastasis. The screening-based approach uniquely enabled by our approach will likely discover new targets for therapeutic intervention that would have been missed in traditional approaches which don't allow an examination of the complex interactions between cancer cells, stromal cells and the extracellular matrix.
By employing microengineering technologies and leveraging dominant surface tension forces at micrometer dimensions, new experimental systems that more closely model tissues in the body can be designed and applied to improve our ability to study cancer metastasis. These advanced systems will be useful and efficient for acquiring more knowledge and deeper understanding of how and why cancer tumors spread to other locations in the body, and will ultimately help scientists discover new drugs and therapies for improving the long-term health of individuals diagnosed with cancer.
