A reductionist metastasis‐on‐a‐chip platform for in vitro tumor progression modeling and drug screening
Open accessAbstract
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.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Skardal's group demonstrated a 2-organoid metastasis-on-a-chip platform in which CRC cells from colon organoids diffuse into circulation and settle on downstream liver organoids.
“Skardal’s group demonstrated the utility of a 2-organoid metastasis-on-a-chip (MOC) platform224. By using microfluidics to provide circulating flow through the organoid system, tumor cells grow in the primary focus and enter the circulation, with the result that CRC cells of the colon organoids diffuse into the circulation, and then the transferred cells settle on the downstream liver organoids.”
From Tumor-on-a-chip: from bioinspired design to biomedical application (2021) · cites this paper as [224]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Molecular Mechanisms of Stress-Responsive Changes in Collagen and Elastin Networks in Skin
Aziz, J., Shezali, H., Radzi, Z., Yahya, N. A., Abu Kassim, N. H., Czernuszka, J., & Rahman, M. T. (2016) · Skin Pharmacology and Physiology · doi:10.1159/000447017 · Cited by 7,323 · see citing works
Younan Xia, A., & Whitesides, G. M. (1998) · Annual Review of Materials Science · doi:10.1146/annurev.matsci.28.1.153 · Cited by 4,610 · see citing works
Matrix Crosslinking Forces Tumor Progression by Enhancing Integrin Signaling
Levental, K. R., Yu, H., Kass, L., Lakins, J. N., Egeblad, M., Erler, J. T., Fong, S. F. T., Csiszar, K., Giaccia, A., Weninger, W., et al. (2009) · Cell · doi:10.1016/j.cell.2009.10.027 · Cited by 4,101 · see citing works
Hyaluronic Acid Hydrogels for Biomedical Applications
Burdick, J. A., & Prestwich, G. D. (2011) · Advanced Materials · doi:10.1002/adma.201003963 · Cited by 2,150 · see citing works
Zaman, M. H., Trapani, L. M., Sieminski, A. L., MacKellar, D. C., Gong, H., Kamm, R. D., Wells, A. H., Lauffenburger, D. A., & Matsudaira, P. T. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0604460103 · Cited by 1,159 · see citing works
The use of 3-d cultures for high-throughput screening: the multicellular spheroid model.
Kunz-Schughart, L. A., Freyer, J. P., Hofstaedter, F., & Ebner, R. (2004) · SLAS DISCOVERY · doi:10.1177/1087057104265040 · Cited by 797 · see citing works
Engineered In Vitro Disease Models
Benam, K. H., Dauth, S., Hassell, B., Herland, A., Jain, A., Jang, K.-J., Karalis, K., Kim, H. J., MacQueen, L., Mahmoodian, R., et al. (2015) · Annual Review of Pathology: Mechanisms of Disease · doi:10.1146/annurev-pathol-012414-040418 · Cited by 554 · see citing works
Evaluation of hydrogels for bio‐printing applications
Murphy, S. V., Skardal, A., & Atala, A. (2012) · Journal of Biomedical Materials Research Part A · doi:10.1002/jbm.a.34326 · Cited by 547 · see citing works
Self-citationOršulić, S., Huber, O., Aberle, H., Arnold, S. J., & Kemler, R. (1999) · Journal of Cell Science · doi:10.1242/jcs.112.8.1237 · Cited by 534 · see citing works
Skardal, A., Zhang, J., & Prestwich, G. D. (2010) · Biomaterials · doi:10.1016/j.biomaterials.2010.04.045 · Cited by 465 · see citing works
Self-citationPhotocrosslinkable Hyaluronan-Gelatin Hydrogels for Two-Step Bioprinting
Skardal, A., Zhang, J., McCoard, L., Xu, X., Oottamasathien, S., & Prestwich, G. D. (2010) · Tissue Engineering Part A · doi:10.1089/ten.tea.2009.0798 · Cited by 425 · see citing works
Self-citationPrestwich, G. D. (2011) · Journal of Controlled Release · doi:10.1016/j.jconrel.2011.04.007 · Cited by 415 · see citing works
Review. Hyaluronan: A Powerful Tissue Engineering Tool
Allison, D. D., & Grande-Allen, K. J. (2006) · Tissue Engineering · doi:10.1089/ten.2006.12.2131 · Cited by 400 · see citing works
Standing the test of time: targeting thymidylate biosynthesis in cancer therapy
Wilson, P. M., Danenberg, P. V., Johnston, P. G., Lenz, H., & Ladner, R. D. (2014) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2014.51 · Cited by 391 · see citing works
Tumor Cell-Organ Microenvironment Interactions in the Pathogenesis of Cancer Metastasis
Langley, R. R., & Fidler, I. J. (2007) · Endocrine Reviews · doi:10.1210/er.2006-0027 · Cited by 368 · see citing works
Epithelial to mesenchymal transition inducing transcription factors and metastatic cancer
Tania, M., Khan, M. A., & Fu, J. (2014) · Tumor Biology · doi:10.1007/s13277-014-2163-y · Cited by 257 · see citing works
Dynamically Crosslinked Gold Nanoparticle – Hyaluronan Hydrogels
Skardal, A., Zhang, J., McCoard, L., Oottamasathien, S., & Prestwich, G. D. (2010) · Advanced Materials · doi:10.1002/adma.201001436 · Cited by 248 · see citing works
Self-citationControl of β‐Catenin Signaling in Tumor Development
Behrens, J. (2000) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2000.tb06698.x · Cited by 229 · see citing works
Organs-on-a-chip: a new tool for drug discovery
Polini, A., Prodanov, L., Bhise, N. S., Manoharan, V., Dokmeci, M. R., & Khademhosseini, A. (2014) · Expert Opinion on Drug Discovery · doi:10.1517/17460441.2014.886562 · Cited by 223 · see citing works
TCF: Lady Justice Casting the Final Verdict on the Outcome of Wnt Signalling
Brantjes, H., Barker, N., van Es, J. H., & Clevers, H. C. (2002) · Biological Chemistry · doi:10.1515/bc.2002.027 · Cited by 202 · see citing works
Tissue specific synthetic ECM hydrogels for 3-D in vitro maintenance of hepatocyte function
Skardal, A., Smith, L., Bharadwaj, S., Atala, A., Soker, S., & Zhang, Y. (2012) · Biomaterials · doi:10.1016/j.biomaterials.2012.03.034 · Cited by 183 · see citing works
Self-citationKarlsson, H., Fryknäs, M., Larsson, R., & Nygren, P. (2012) · Experimental Cell Research · doi:10.1016/j.yexcr.2012.03.026 · Cited by 180 · see citing works
Prestwich, G. D. (2007) · Accounts of Chemical Research · doi:10.1021/ar7000827 · Cited by 176 · see citing works
Prestwich, G. D. (2007) · Journal of Cellular Biochemistry · doi:10.1002/jcb.21386 · Cited by 151 · see citing works
The role of the organ microenvironment in the biology and therapy of cancer metastasis
Fidler, I. J., Kim, S., & Langley, R. R. (2006) · Journal of Cellular Biochemistry · doi:10.1002/jcb.21148 · Cited by 143 · see citing works
Chemically-Modified HA for Therapy and Regenerative Medicine
Prestwich, G. D., & Kuo, J.-W. (2008) · Current Pharmaceutical Biotechnology · doi:10.2174/138920108785161523 · Cited by 139 · see citing works
Liver-Tumor Hybrid Organoids for Modeling Tumor Growth and Drug Response In Vitro
Skardal, A., Devarasetty, M., Rodman, C., Atala, A., & Söker, S. (2015) · Annals of Biomedical Engineering · doi:10.1007/s10439-015-1298-3 · Cited by 138 · see citing works
Self-citationThree-dimensional culture of hepatocytes on porcine liver tissue-derived extracellular matrix
Lang, R., Stern, M. M., Smith, L., Liu, Y., Bharadwaj, S., Liu, G., Baptista, P. M., Bergman, C. R., Söker, S., Yoo, J. J., et al. (2011) · Biomaterials · doi:10.1016/j.biomaterials.2011.06.005 · Cited by 136 · see citing works
Self-citationDrewitz, M., Helbling, M. M., Fried, N., Bieri, M., Moritz, W., Lichtenberg, J., & Kelm, J. M. (2011) · Biotechnology Journal · doi:10.1002/biot.201100290 · Cited by 124 · see citing works
Ho, W. J., Pham, E. A., Kim, J. W., Ng, C. W., Kim, J. H., Kamei, D. T., & Wu, B. M. (2010) · Cancer Science · doi:10.1111/j.1349-7006.2010.01723.x · Cited by 115 · see citing works
Zhang, J., Skardal, A., & Prestwich, G. D. (2008) · Biomaterials · doi:10.1016/j.biomaterials.2008.08.008 · Cited by 108 · see citing works
Self-citationSkardal, A., Sarker, S. F., Crabbé, A., Nickerson, C. A., & Prestwich, G. D. (2010) · Biomaterials · doi:10.1016/j.biomaterials.2010.07.047 · Cited by 101 · see citing works
Self-citationIn situ patterned micro 3D liver constructs for parallel toxicology testing in a fluidic device
Skardal, A., Devarasetty, M., Söker, S., & Hall, A. R. (2015) · Biofabrication · doi:10.1088/1758-5090/7/3/031001 · Cited by 86 · see citing works
Self-citationKarakiulakis, G., Papanikolaou, C., Јаnkovic, S., et al. (1997) · PubMed · Cited by 73 · see citing works
McGrail, D. J., Mezencev, R., Kieu, Q. M. N., McDonald, J. F., & Dawson, M. (2014) · The FASEB Journal · doi:10.1096/fj.14-257345 · Cited by 60 · see citing works
Krubasik, D., Iyer, N. G., English, W., Ahmed, A. A., Vias, M., Roskelley, C. D., Brenton, J. D., Caldas, C., & Murphy, G. (2006) · British Journal of Cancer · doi:10.1038/sj.bjc.6603101 · Cited by 49 · see citing works
Franci, C., Zhou, J., Jiang, Z., Modrusan, Z. D., Good, Z., Jackson, E. L., & Kouros‐Mehr, H. (2013) · PLoS ONE · doi:10.1371/journal.pone.0058183 · Cited by 43 · see citing works
Colorectal hepatic metastasis: Evolving therapies
Macedo, F. I. (2014) · World Journal of Hepatology · doi:10.4254/wjh.v6.i7.453 · Cited by 15 · see citing works
Coordinating changes in cell adhesion and phenotype during EMT-like processes in cancer
Gavert, N. S., & Ben‐Ze'ev, A. (2010) · F1000 Biology Reports · doi:10.3410/b2-86 · Cited by 8 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Human organs-on-chips for disease modelling, drug development and personalized medicine
Ingber, D. E. (2022) · Nature Reviews Genetics · doi:10.1038/s41576-022-00466-9 · Cited by 1,589 · see citing works
Multi-tissue interactions in an integrated three-tissue organ-on-a-chip platform
Skardal, A., Murphy, S. V., Devarasetty, M., Mead, I., Kang, H.-W., Seol, Y.-J., Shrike Zhang, Y., Shin, S.-R., Zhao, L., Aleman, J., et al. (2017) · Scientific Reports · doi:10.1038/s41598-017-08879-x · Cited by 623 · see citing works
Self-citationOrganoid-on-a-chip and body-on-a-chip systems for drug screening and disease modeling
Skardal, A., Shupe, T., & Atala, A. (2016) · Drug Discovery Today · doi:10.1016/j.drudis.2016.07.003 · Cited by 512 · see citing works
Self-citationOrgan-on-a-chip platforms: a convergence of advanced materials, cells, and microscale technologies
Ahadian, S., Civitarese, R., Bannerman, D., Mohammadi, M. H., Lu, R., Wang, E., Davenport‐Huyer, L., Lai, B., Zhang, B., Zhao, Y., et al. (2018) · Advanced Healthcare Materials · doi:10.1002/adhm.201700506 · Cited by 315 · see citing works
Tumor-on-a-chip: from bioinspired design to biomedical application
Liu, X., Fang, J., Huang, S., Wu, X., Xie, X., Wang, J., Liu, F., Zhang, M., Peng, Z., & Hu, N. (2021) · Microsystems & Nanoengineering · doi:10.1038/s41378-021-00277-8 · Cited by 246 · see citing works
Organ-on-chip models of cancer metastasis for future personalized medicine: From chip to the patient
Caballero, D., Kaushik, S., Correlo, V. M., Oliveira, J. M., Reis, R. L., & Kundu, S. C. (2017) · Biomaterials · doi:10.1016/j.biomaterials.2017.10.005 · Cited by 221 · see citing works
Trujillo-de Santiago, G., Flores-Garza, B. G., Tavares-Negrete, J. A., Lara-Mayorga, I. M., González-Gamboa, I., Zhang, Y. S., Rojas-Martínez, A., Ortiz-López, R., & Álvarez, M. M. (2019) · Materials · doi:10.3390/ma12182945 · Cited by 184 · see citing works
Aleman, J., & Skardal, A. (2019) · Biotechnology and Bioengineering · doi:10.1002/bit.26871 · Cited by 160 · see citing works
Self-citationApplications of tumor chip technology
Hachey, S. J., & Hughes, C. C. W. (2018) · Lab on a Chip · doi:10.1039/c8lc00330k · Cited by 128 · see citing works
Environmental Toxin Screening Using Human-Derived 3D Bioengineered Liver and Cardiac Organoids
Forsythe, S. D., Devarasetty, M., Shupe, T., Bishop, C., Atala, A., Soker, S., & Skardal, A. (2018) · Frontiers in Public Health · doi:10.3389/fpubh.2018.00103 · Cited by 112 · see citing works
Self-citationOrgans-on-a-chip: a union of tissue engineering and microfabrication
Zhao, Y., Wang, E. Y., Lai, F. B. L., Cheung, K., & Radisic, M. (2023) · Trends in Biotechnology · doi:10.1016/j.tibtech.2022.12.018 · Cited by 93 · see citing works
Wang, Y., Wu, D., Wu, G., Wu, J., Lu, S., Lo, J., He, Y., Zhao, C., Zhao, X., Zhang, H., et al. (2020) · Theranostics · doi:10.7150/thno.38736 · Cited by 93 · see citing works
Fan, T. M., Roberts, R. D., & Lizardo, M. M. (2020) · Frontiers in Oncology · doi:10.3389/fonc.2020.00013 · Cited by 90 · see citing works
- Authors
- Skardal, A., Devarasetty, M., Forsythe, S., Atala, A., & Soker, S.
- Affiliations
- Atrium Health Wake Forest Baptist (US)
- Wake Forest Institute for Regenerative Medicine Wake Forest School of Medicine, Medical Center Boulevard Winston‐Salem North Carolina
- Corresponding author
- Skardal, Aleksander
- Venue
- Biotechnology and Bioengineering
- Publisher
- Wiley
- Published
- 2016-03-08
- Volume
- 113
- Issue
- 9
- Pages
- 2020-2032
- ISSN
- 0006-3592 (ISSN-L)
- 1097-0290
- PMC
- PMC5778914
- OpenAlex
- W2283306732
- Cited by
- 230
- References
- 39
- Citations by year
- 2026: 10 · 2025: 17 · 2024: 22 · 2023: 29 · 2022: 31 · 2021: 34 · 2020: 26 · 2019: 18 · 2018: 22 · 2017: 18 · 2016: 3
- FWCI
- 9.79
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Biotechnology and Bioengineering (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Golfers Against Cancer
- Topics
- Physical Sciences › Engineering › Biomedical Engineering › 3D Printing in Biomedical Research
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Medicine › Hydrogels: synthesis, properties, applications
- Keywords
- colon cancer metastasis, liver metastasis, hyaluronic acid hydrogel, organ-on-a-chip, tumor cell migration, tumor microenvironment, hydrogel mechanical properties, mesenchymal phenotype
- MeSH terms
- Animals, Drug Evaluation, Preclinical, Humans, Models, Biological, Neoplasm Metastasis, Neoplasms, Hydrogels, HCT116 Cells, Cell Line, Tumor, Microfluidic Analytical Techniques, Tissue Array Analysis, Mice, Hep G2 Cells
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
