This application addresses PQ #24: Given the difficulty of studying metastasis, can we develop new approaches, such as engineered tissue grafts, to investigate the biology of tumor spread? Many of the steps in the metastatic process, specifically invasion, intravasation, and extravasation, take place at or near the interface between the local tissue microenvironment and the vascular system. Therefore the development of a platform that combines both extracellular matrix and a vessel is key to unraveling the events that guide the development of metastasis. The major challenge in developing such a platform is the complexity of this interface. To address this challenge we propose a microfluidic platform that incorporates both artificial extra cellular matrix and a vessel. Our objective is to produce a platform that: (1) recapitulates the relevant physical and biological characteristics of the interface between extracellular matrix and a vessel in a physiologically relevant geometry, (2) allows control over physicochemical and biological properties such that experiments can be performed systematically and reproducibly, and allowing variables to be adjusted independently, and (3) is sufficiently robust that fabrication can be readily translated to other laboratories. In preliminary data we have demonstrated fabrication of a functional platform and the feasibility of using the platform to study metastasis. In this research, we propose to lay the foundations for the refinement and further development of the platform to enable advances in the understanding of metastasis. The artificial extra cellular matrix/vessel platform allows study of invasion, intravasation and extravasation in a physiologically relevant geometry. To study invasion and intravasation a cavity is created in the extra cellular matrix near the artificial vessel. Prolifertion, detachment, and migration of cancer cells to the vessel, followed by intravasation into the vessel, can be imaged in real time. To study extravasation, cancer cells are added to the perfusion media flowing through the vessel. Depending on the vessel size, arrest can occur by adhesion or occlusion. In preliminary data, we have performed a proof-of-principle demonstration of the formation of a perfused artificial vessel using vascular endothelial cells and the incorporation of a tumor for the study of invasion and intravasation. The overall goal of this project is to develop an engineered ECM/vessel platform for the systematic study of key steps in the metastatic cascade. Building on these results we will optimize the engineered ECM/vessel platform (Aim 1), study the dynamics of invasion and intravasation (Aim 2a) and extravasation (Aim 2b), and develop modules for the translation of the engineered ECM/vessel platform for the study of metastasis (Aim 3).
We propose to develop an engineered platform to study the steps involved in the spread of cancer. Since metastasis is responsible for most cancer related deaths, such a platform could be key to the development of new therapies to prevent the spread of cancer. The engineered platform includes a vessel embedded in surrounding extra cellular matrix and allows all relevant biological and physico-chemical variables to be independently controlled and systematically studied.
|Katt, Moriah E; Wong, Andrew D; Searson, Peter C (2018) Dissemination from a Solid Tumor: Examining the Multiple Parallel Pathways. Trends Cancer 4:20-37|
|Wong, Andrew D; Searson, Peter C (2017) Mitosis-Mediated Intravasation in a Tissue-Engineered Tumor-Microvessel Platform. Cancer Res 77:6453-6461|
|DeStefano, Jackson G; Williams, Ashley; Wnorowski, Alexa et al. (2017) Real-time quantification of endothelial response to shear stress and vascular modulators. Integr Biol (Camb) 9:362-374|
|Bogorad, Max I; Searson, Peter C (2016) Real-time imaging and quantitative analysis of doxorubicin transport in a perfusable microvessel platform. Integr Biol (Camb) 8:976-84|
|Katt, Moriah E; Xu, Zinnia S; Gerecht, Sharon et al. (2016) Human Brain Microvascular Endothelial Cells Derived from the BC1 iPS Cell Line Exhibit a Blood-Brain Barrier Phenotype. PLoS One 11:e0152105|
|Katt, Moriah E; Placone, Amanda L; Wong, Andrew D et al. (2016) In Vitro Tumor Models: Advantages, Disadvantages, Variables, and Selecting the Right Platform. Front Bioeng Biotechnol 4:12|
|Kraya, Ramsey; Komin, Alexander; Searson, Peter (2016) On Chip Bioelectric Impedance Spectroscopy Reveals the Effect of P-Glycoprotein Efflux Pumps on the Paracellular Impedance of Tight Junctions at the Blood-Brain Barrier. IEEE Trans Nanobioscience 15:697-703|
|Huang, Yu-Ja; Hoffmann, Gwendolyn; Wheeler, Benjamin et al. (2016) Cellular microenvironment modulates the galvanotaxis of brain tumor initiating cells. Sci Rep 6:21583|
|Wong, Andrew D; Ye, Mao; Ulmschneider, Martin B et al. (2015) Quantitative Analysis of the Enhanced Permeation and Retention (EPR) Effect. PLoS One 10:e0123461|
|Reinitz, Adam; DeStefano, Jackson; Ye, Mao et al. (2015) Human brain microvascular endothelial cells resist elongation due to shear stress. Microvasc Res 99:8-18|
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