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Organ-specific metastases obtained by culturing colorectal cancer cells on tissue-specific decellularized scaffolds

Nature Biomedical Engineering volume 2, pages 443–452 (2018)Cite this article

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Abstract

Metastatic disease remains the primary cause of mortality in cancer patients. Yet the number of available in vitro models to study metastasis is limited by challenges in the recapitulation of the metastatic microenvironment in vitro, and by difficulties in maintaining colonized-tissue specificity in the expansion and maintenance of metastatic cells. Here, we show that decellularized scaffolds that retain tissue-specific extracellular-matrix components and bound signalling molecules enable, when seeded with colorectal cancer cells, the spontaneous formation of three-dimensional cell colonies that histologically, molecularly and phenotypically resemble in vivo metastases. Lung and liver metastases obtained by culturing colorectal cancer cells on, respectively, lung and liver decellularized scaffolds retained their tissue-specific tropism when injected in mice. We also found that the engineered metastases contained signet ring cells, which has not previously been observed ex vivo. A culture system with tissue-specific decellularized scaffolds represents a simple and powerful approach for the study of organ-specific cancer metastases.

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Fig. 1: BMSs recapitulate tissue-specific microenvironments found in vivo.
Fig. 2: CRC cells spontaneously form 3D engineered metastases when cultured on liver and lung BMSs.
Fig. 3: Engineered liver metastases are comparable to liver metastases found in vivo.
Fig. 4: Engineered metastases demonstrate increased metastatic potential in vivo.
Fig. 5: CRC cells grown on different substratas respond differently to chemotherapeutics and radiotherapy.

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Acknowledgements

The authors thank Microscopy Service Laboratory, Animal Studies Core, Genomics Core Facility, and Animal Histopathology Core Facility at the University of North Carolina at Chapel Hill. This work was supported by the University Cancer Research Fund from the University of North Carolina and by R21 CA182322 from the National Institutes of Health/National Cancer Institute. This work was also supported by a generous gift from Mr and Mrs E. Barkley. L.Z. was supported by two funds from the National Natural Science Foundation of China (no. 81372424 and no. 81071831) and the Foundation Research Project of Jiangsu Province (no. BK20131131).

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Authors and Affiliations

  1. Laboratory of Nano- and Translational Medicine, Department of Radiation Oncology, Lineberger Comprehensive Cancer Center, Carolina Center for Cancer Nanotechnology Excellence, Carolina Institute of Nanomedicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Xi Tian, Michael E. Werner, Kyle C. Roche, Henry P. Foote, Stephanie K. Yu, Samuel B. Warner, Jonathan A. Copp, Haydee Lara, Joseph M. Caster, Joel E. Tepper & Andrew Z. Wang

  2. Department of Cell and Molecular Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Ariel D. Hanson, Eliane L. Wauthier & Lola M. Reid

  3. Department of Pharmacology, UNC Proteomics Core Facility, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Laura E. Herring

  4. Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Affiliated Hospital of Xuzhou Medical College, Cancer Institute of Xuzhou Medical College, Jiangsu, China

    Longzhen Zhang

  5. Division of Medical Oncology, Department of Medicine, Duke Cancer Institute, Duke University Medical Center, Durham, NC, USA

    David S. Hsu & Tian Zhang

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  1. Xi Tian
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Contributions

X.T., M.E.W., K.C.R., H.P.F., S.K.Y., J.A.C., H.L. and L.Z. performed the experiments. X.T., M.E.W., H.P.F. and L.E.H. analysed data. A.D.H., S.B.W., E.L.W. and D.S.H. provided essential protocols and technical support. X.T., M.E.W., K.C.R., T.Z. and A.Z.W. designed the experiments. X.T., M.E.W., K.C.R., H.P.F. and A.Z.W. wrote the manuscript. X.T., A.D.H., K.C.R., J.E.T., J.M.C., T.Z., L.M.R. and A.Z.W. edited the manuscript. A.Z.W. directed the study.

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Correspondence to Andrew Z. Wang.

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Tian, X., Werner, M.E., Roche, K.C. et al. Organ-specific metastases obtained by culturing colorectal cancer cells on tissue-specific decellularized scaffolds. Nat Biomed Eng 2, 443–452 (2018). https://doi.org/10.1038/s41551-018-0231-0

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