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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21CA182322-02
Application #
8737824
Study Section
Special Emphasis Panel (ZCA1)
Program Officer
Knowlton, John R
Project Start
2013-09-19
Project End
2016-08-31
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
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Min, Yuanzeng; Roche, Kyle C; Tian, Shaomin et al. (2017) Antigen-capturing nanoparticles improve the abscopal effect and cancer immunotherapy. Nat Nanotechnol 12:877-882
Tian, Jing; Min, Yuangzeng; Rodgers, Zachary et al. (2017) Nanoparticle delivery of chemotherapy combination regimen improves the therapeutic efficacy in mouse models of lung cancer. Nanomedicine 13:1301-1307
Wang, Chao; Sun, Wujin; Wright, Grace et al. (2016) Inflammation-Triggered Cancer Immunotherapy by Programmed Delivery of CpG and Anti-PD1 Antibody. Adv Mater 28:8912-8920
Reid, Lola M (2016) Stem/progenitor cells and reprogramming (plasticity) mechanisms in liver, biliary tree, and pancreas. Hepatology 64:4-7
Carpino, Guido; Renzi, Anastasia; Franchitto, Antonio et al. (2016) Stem/Progenitor Cell Niches Involved in Hepatic and Biliary Regeneration. Stem Cells Int 2016:3658013
Carpino, Guido; Renzi, Anastasia; Cardinale, Vincenzo et al. (2016) Progenitor cell niches in the human pancreatic duct system and associated pancreatic duct glands: an anatomical and immunophenotyping study. J Anat 228:474-86
Oikawa, Tsunekazu; Wauthier, Eliane; Dinh, Timothy A et al. (2015) Model of fibrolamellar hepatocellular carcinomas reveals striking enrichment in cancer stem cells. Nat Commun 6:8070
Ji, Junfang; Zheng, Xin; Forgues, Marshonna et al. (2015) Identification of microRNAs specific for epithelial cell adhesion molecule-positive tumor cells in hepatocellular carcinoma. Hepatology 62:829-40
Harrill, Joshua A; Parks, Bethany B; Wauthier, Eliane et al. (2015) Lineage-dependent effects of aryl hydrocarbon receptor agonists contribute to liver tumorigenesis. Hepatology 61:548-60

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