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Invasive three-dimensional organotypic neoplasia from multiple normal human epithelia

Abstract

Refined cancer models are required if researchers are to assess the burgeoning number of potential targets for cancer therapeutics in a clinically relevant context that allows a fast turnaround. Here we use tumor-associated genetic pathways to transform primary human epithelial cells from the epidermis, oropharynx, esophagus and cervix into genetically defined tumors in a human three-dimensional (3D) tissue environment that incorporates cell-populated stroma and intact basement membrane. These engineered organotypic tissues recapitulated natural features of tumor progression, including epithelial invasion through basement membrane, a complex process that is necessary for biological malignancy in 90% of human cancers. Invasion was rapid and was potentiated by stromal cells. Oncogenic signals in 3D tissue, but not 2D culture, resembled gene expression profiles from spontaneous human cancers. We screened 3D organotypic neoplasia with well-characterized signaling pathway inhibitors to distill a clinically faithful cancer gene signature. Multitissue 3D human tissue cancer models may provide an efficient and relevant complement to current approaches to characterizing cancer progression.

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Figure 1: 3D organotypic human epithelial tissue.
Figure 2: Organotypic neoplasia from multiple stratified epithelia.
Figure 3: Stromal cells potentiate invasion in organotypic neoplasia.
Figure 4: Analysis of organotypic neoplasia.

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Gene Expression Omnibus

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Acknowledgements

This work was supported by National Institutes of Health grant AR43799 to P.A.K. We thank A. Oro, P. Marinkovich, H. Chang, D. Felsher, S. Artandi, A. Sweet-Cordero, M. Scott, G. Sen, Z. Siprashvili, M. Kretz and J. Reuter for presubmission review of the manuscript. T.W.R. is the recipient of career development award National Institutes of Health K08AR053195.

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Contributions

T.W.R. designed the experiments, performed research, interpreted data and wrote the manuscript. J.M.C. performed experiments. D.J.W. helped to analyze expression array data. P.A.K. helped design and interpret experiments and helped write the manuscript.

Corresponding author

Correspondence to Paul A Khavari.

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The authors declare no competing financial interests.

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Supplementary Figures 1–8, Supplementary Tables 1–5 and Supplementary Methods (PDF 2632 kb)

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Ridky, T., Chow, J., Wong, D. et al. Invasive three-dimensional organotypic neoplasia from multiple normal human epithelia. Nat Med 16, 1450–1455 (2010). https://doi.org/10.1038/nm.2265

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