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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA186134-03
Application #
9194394
Study Section
Instrumentation and Systems Development Study Section (ISD)
Program Officer
Woodhouse, Elizabeth
Project Start
2015-01-12
Project End
2019-12-31
Budget Start
2017-01-01
Budget End
2017-12-31
Support Year
3
Fiscal Year
2017
Total Cost
$563,022
Indirect Cost
$189,858
Name
University of Wisconsin Madison
Department
Biomedical Engineering
Type
Schools of Engineering
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Morgan, Molly M; Johnson, Brian P; Livingston, Megan K et al. (2016) Personalized in vitro cancer models to predict therapeutic response: Challenges and a framework for improvement. Pharmacol Ther 165:79-92
Jiménez-Torres, José A; Peery, Stephen L; Sung, Kyung E et al. (2016) LumeNEXT: A Practical Method to Pattern Luminal Structures in ECM Gels. Adv Healthc Mater 5:198-204