In order to translate the findings from basic cellular research into clinical applications, cell-based models need to recapitulate both the 3D organization and multicellular complexity of an organ but at the same time accommodate systematic experimental intervention. Here we describe a hierarchy of tractable 3D models that range in complexity from organotypic 3D cultures (both monotypic and multicellular) to animal-based recombinations in vivo. Implementation of these physiologically relevant models, illustrated here in the context of human epithelial tissues, has enabled the study of intrinsic cell regulation pathways and also has provided compelling evidence for the role of the stromal compartment in directing epithelial cell function and dysfunction. Furthermore the experimental accessibility afforded by these tissue-specific 3D models has implications for the design and development of cancer therapies.
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