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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.

SUBMITTER: Skardal A

PROVIDER: S-EPMC5778914 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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A reductionist metastasis-on-a-chip platform for in vitro tumor progression modeling and drug screening.

Skardal Aleksander A Devarasetty Mahesh M Forsythe Steven S Atala Anthony A Soker Shay S

Biotechnology and bioengineering 20160308 9

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 const ...[more]

PMID: 26888480

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Project description:Tumor-infiltrating leukocytes, in particular macrophages, play an important role in tumor behavior and clinical outcome. The spectrum of macrophage subtypes ranges from antitumor 'M1'-type to protumor 'M2'-type macrophages. Tumor-associated macrophages (TAMs) typically display phenotypic features of both M1 and M2, and the population distribution is thought to be dynamic and evolves as the tumor progresses. However, our understanding of how TAMs impact the tumor microenvironment remains limited by the lack of appropriate 3D in vitro models that can capture cell-cell dynamics at high spatial and temporal resolution. Using our recently developed microphysiological 'tumor-on-a-chip' (TOC) device, we present here our findings on the impact of defined macrophage subsets on tumor behavior. The TOC device design contains three adjacent and connected chambers in which both the upper and lower chambers are loaded with tumor cells, whereas the central chamber contains a dynamic, perfused, living microvascular network. Introduction of human pancreatic or colorectal cancer cells together with M1-polarized macrophages significantly inhibited tumor growth and tumor-induced angiogenesis. Protein analysis and antibody-based neutralization studies confirmed that these effects were mediated through production of C-X-C motif chemokines (CXCL9), CXCL10 and CXCL11. By contrast, M2-macrophages mediated increased tumor cell migration into the vascularized chamber and did not inhibit tumor growth or angiogenesis. In fact, single-cell RNA sequencing showed that M2 macrophages further segregated endothelial cells into two distinct subsets, corresponding to static cells in vessels versus active cells involved in angiogenesis. The impact of M2 macrophages was mediated mostly by production of matrix metalloproteinase 7 and angiopoietin 2. In summary, our data demonstrate the utility of the TOC device to mechanistically probe biological questions in a 3D in vitro microenvironment.

Project description:Metastasis is the cause of most triple-negative breast cancer deaths, yet anti-metastatic therapeutics remain limited. To develop new therapeutics to prevent metastasis, pathophysiologically relevant assays that recapitulate tumor microenvironment is essential for disease modeling and drug discovery. Here, we have developed a microfluidic metastasis-on-chip assay of the early stages of cancer metastasis integrated with the triple-negative breast cancer cell line (MDA-MB-231), stromal fibroblasts and a perfused microvessel. High-content imaging with automated quantification methods was optimized to assess the tumor cell invasion and intravasation within the model. Cell invasion and intravasation were enhanced when fibroblasts co-cultured with a breast cancer cell line (MDA-MB-231). However, the non-invasive breast cancer cell line, MCF7, remained non-invasive in our model, even in the presence of fibroblasts. High-content screening of a targeted anti-cancer therapy drug library was conducted to evaluate the drug response sensitivity of the optimized model. Through this screening, we identified 30 compounds that reduced the tumor intravasation by 60% compared to controls. Multi-parametric phenotypic analysis was applied by combining the data from the metastasis-on-chip, cell proliferation and 2D cell migration screens, revealing that the drug library was clustered into eight distinct groups with similar drug responses. Notably, MEK inhibitors were enriched in cluster cell invasion and intravasation. In contrast, drugs with molecular targets: ABL, KIT, PDGF, SRC, and VEGFR were enriched in the drug clusters showing a strong effect on tumor cell intravasation with less impact on cell invasion or cell proliferation, of which, Imatinib, a multi-kinase inhibitor targeting BCR-ABL/PDGFR/KIT. Further experimental analysis showed that Imatinib enhanced endothelial barrier stability as measured by trans-endothelial electrical resistance and significantly reduced the trans-endothelial invasion activity of tumor cells. Our findings demonstrate the potential of our metastasis-on-chip assay as a powerful tool for studying cancer metastasis biology, drug discovery aims, and assessing drug responses, offering prospects for personalized anti-metastatic therapies for triple-negative breast cancer patients.

Dataset Information

A reductionist metastasis-on-a-chip platform for in vitro tumor progression modeling and drug screening.

Publications

A reductionist metastasis-on-a-chip platform for in vitro tumor progression modeling and drug screening.

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