A reductionist metastasis‐on‐a‐chip platform for in vitro tumor progression modeling and drug screening. Issue 9 (8th March 2016)

• Record Type: Journal Article
• Authors: Skardal, Aleksander; Devarasetty, Mahesh; Forsythe, Steven; Atala, Anthony; Soker, Shay
• Is Part Of: Biotechnology and bioengineering. Volume 113:Issue 9(2016)
• Page Start: 2020
• Page End: 2032
• Publication Date: 2016-03-08
• Subjects: cancer -- in vitro models -- organs‐on‐a‐chip -- diagnostics -- hydrogel; Biotechnology -- Periodicals; Bioengineering -- Periodicals; 660.6
• DOI: 10.1002/bit.25950
• Languages: English
• ISSNs: 0006-3592

Abstract

ABSTRACT: Current animal and 2‐D cell culture models employed in metastasis research and drug discovery remain poor mimics of human cancer physiology. Here we describe a "metastasis‐on‐a‐chip" system allowing real time tracking of fluorescent colon cancer cells migrating from hydrogel‐fabricated gut constructs to downstream liver constructs within a circulatory fluidic device system that responds to environmental manipulation and drug treatment. Devices consist of two chambers in which gut and liver constructs are housed independently, but are connected in series via circulating fluid flow. Constructs were biofabricated with a hyaluronic acid‐based hydrogel system, capable of a variety of customizations, inside of which representative host tissue cells were suspended and metastatic colon carcinoma tumor foci were created. The host tissue of the constructs expressed normal epithelial markers, which the tumor foci failed to express. Instead, tumor regions lost membrane‐bound adhesion markers, and expressed mesenchymal and proliferative markers, suggesting a metastatic phenotype. Metastatic tumor foci grew in size, eventually disseminating from the intestine construct and entering circulation, subsequently reaching in the liver construct, thus mimicking some of the migratory events observed during metastasis. Lastly, we demonstrated the ability to manipulate the system, including chemically modulating the hydrogel system mechanical properties and administering chemotherapeutic agents, and evaluated the effects of these parameters on invasive tumor migration. These results describe the capability of this early stage metastasis‐on‐a‐chip system to model several important characteristics of human metastasis, thereby demonstrating the potential of the platform for making meaningful advances in cancer investigation and drug discovery. Biotechnol. Bioeng. 2016;113: 2020–2032. © 2016 Wiley Periodicals, Inc. Abstract : In this set of experiments, the authors demonstrate a hydrogel‐supported, engineered multi‐construct system in a fluidic device platform—a "Metastasis‐on‐a‐Chip" (MOC)—to recapitulate colon carcinoma metastasis from the gut to the liver. The MOC system supports live imaging and tracking of tumor growth and progression from one construct to another, the capability to assess the influences of the tumor microenvironment on tumor cell migration, and simple to perform drug treatment screens. Such systems hold immense potential for applications in drug screening, toxicology studies, and personalized medicine.