Understanding the biology of cancer metastases is critical to improving the treatment of cancer. A key challenge in these efforts has been the lack of easy-to-use tumor models that can recapitulate the metastatic disease condition or process. Current models are either too difficult to study or unable to replicate the complex microenvironment of tumor metastasis. Our application aims to address the need for models of cancer metastasis by applying recent advances in tissue engineering. A recent breakthrough in tissue engineering has been the development of decellularized tissue. One novel technique for generating decellularized tissue, developed by Dr. Reid, preserves growth factors and cytokines that are matrix-bound in addition to the extracellular matrix. Decellularized tissue generated using this technique has been termed biomatrix scaffolds. The Reid group has shown that biomatrix scaffolds are tissue-specific but not species-specific both chemically and functionally. Using biomatrix scaffolds, we have obtained exciting preliminary data. We have found that colorectal cancer cells, HT29, SW480 and CaCO2, can spontaneously form 3D colonies on tissue culture dishes coated with liver and lung biomatrix scaffolds. More importantly, we have demonstrated that treatment responses to chemotherapy and radiotherapy are different between cells grown on liver and lung biomatrix scaffolds. Such organ-specific responses have not been observed with other 3D culture systems. Lastly, we have shown that human primary tumor cells from hepatic metastases of colorectal cancer form significantly more colonies when grown on liver biomatrix in vitro compared to that on lung biomatrix, collagen or plastic. Based on our preliminary data, we hypothesize that we can use biomatrix scaffolds to generate 3D in vitro and ex vivo models of cancer metastasis. In this application, we plan to use colorectal cancer as a model disease and develop models of colorectal cancer with liver and lung metastases. We theorize that our proposed models can recapitulate the biology of colorectal cancer metastasis to liver and lung as well as predict treatment responses of metastases. Our application has two specific aims.
The first aim will focus on the development of in vitro organ-specific 3D models of colorectal cancer metastasis using tissue-specific biomatrix scaffolds only.
Our second aim will focus on the development of 3D ex vivo models of colorectal cancer liver metastases using liver organoids prepared by recellularization of liver biomatrix scaffolds. Success with our research can lead to the development of novel in vitro/ex vivo models of cancer metastasis that can better mimic the disease process. These can become powerful tools for studying the biology of metastasis including: mechanisms of metastasis;roles of physical forces on metastasis;and identification of matrix components controlling metastatic potential. Furthermore, models can be useful for in vitro therapeutic screening assays targeted towards cancer metastasis to a specific organ. Our strategy can also be applied to other types of cancers and metastasis to other organs.

Public Health Relevance

Our proposal aims to apply advances in tissue engineering to address a need in cancer research. We plan to develop 3D in vitro and ex vivo models of cancer metastasis that can closely mimic the in vivo condition. Our models have the potential to advance our understanding of cancer metastasis biology as well as improve our ability to predict treatment response of cancer metastasis.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZCA1-SRLB-Q (O1))
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Knowlton, John R
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University of North Carolina Chapel Hill
Schools of Medicine
Chapel Hill
United States
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Yamane, Daisuke; McGivern, David R; Wauthier, Eliane et al. (2014) Regulation of the hepatitis C virus RNA replicase by endogenous lipid peroxidation. Nat Med 20:927-35