title: A reductionist metastasis-on-a-chip platform for in vitro tumor progression modeling and drug screening.
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.
authors.affiliation: Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, North Carolina. askardal@wakehealth.edu.|Virginia Tech-Wake Forest University School of Biomedical Engineering and Sciences, Wake Forest Baptist Health, Medical Center Boulevard, Winston-Salem, North Carolina. askardal@wakehealth.edu.|Department of Cancer Biology, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, North Carolina 27157. askardal@wakehealth.edu.
authors.forename: Aleksander
authors.initials: A
authors.lastname: Skardal
authors.affiliation: Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, North Carolina.|Virginia Tech-Wake Forest University School of Biomedical Engineering and Sciences, Wake Forest Baptist Health, Medical Center Boulevard, Winston-Salem, North Carolina.
authors.forename: Mahesh
authors.initials: M
authors.lastname: Devarasetty
authors.affiliation: Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, North Carolina.
authors.forename: Steven
authors.initials: S
authors.lastname: Forsythe
authors.affiliation: Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, North Carolina.|Virginia Tech-Wake Forest University School of Biomedical Engineering and Sciences, Wake Forest Baptist Health, Medical Center Boulevard, Winston-Salem, North Carolina.
authors.forename: Anthony
authors.initials: A
authors.lastname: Atala
authors.affiliation: Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, North Carolina.|Virginia Tech-Wake Forest University School of Biomedical Engineering and Sciences, Wake Forest Baptist Health, Medical Center Boulevard, Winston-Salem, North Carolina.|Department of Cancer Biology, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, North Carolina 27157.
authors.forename: Shay
authors.initials: S
authors.lastname: Soker
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004353:Drug Evaluation, Preclinical; D045325:HCT116 Cells; D056945:Hep G2 Cells; D006801:Humans; D020100:Hydrogels; D051379:Mice; D046210:Microfluidic Analytical Techniques / Q000379:methods*; D008954:Models, Biological; D009362:Neoplasm Metastasis / Q000503:physiopathology*; D009369:Neoplasms / Q000378:metabolism*; D046888:Tissue Array Analysis / Q000379:methods*
chemical_list: D020100:Hydrogels
keywords: cancer; diagnostics; hydrogel; in vitro models; organs-on-a-chip