This work was supported by a seed grant from the National Institutes of Health (NIH) Bay Area Physical Sciences and Oncology Center (to Z.J.G. Justin Farlow for help with data analysis, and an anonymous reviewer for helpful comments on the manuscript. Alba de Moniz for technical assistance and comments, Dr. Maija Valta for help in preparing primary prostate organoids, Dr. Our model also predicts that mutations affecting binary cell–ECM interactions are catastrophic and could contribute to loss of tissue architecture in diseases such as breast cancer. Therefore, a binary interfacial interaction with the tissue boundary provides a flexible and generalizable strategy for forming and maintaining the structure of two-component tissues that exhibit abundant heterogeneity and plasticity.

We also find that this mechanism of self-organization is conserved in the human prostate. Using mathematical modeling and cell-type-specific knockdown of key regulators of cell–cell cohesion, we show that this strategy of self-organization is robust to severe perturbations affecting cell–cell contact formation. Surprisingly, interactions with the tissue–ECM boundary are binary, in that only one cell type interacts appreciably with the boundary. We find that self-organization is dominated by the interfacial energy of the tissue–ECM boundary, rather than by differential homo- and heterotypic energies of cell–cell interaction. To investigate the consequences of cellular heterogeneity and plasticity on cell positioning in the mammary gland, we reconstituted its self-organization from aggregates of primary cells in vitro. The ducts and acini of the human mammary gland are prototypical heterogeneous and dynamic tissues comprising two concentrically arranged cell types. However, it is unclear how self-organization by this mechanism remains robust when interfacial energies become heterogeneous in either time or space. Developing tissues contain motile populations of cells that can self-organize into spatially ordered tissues based on differences in their interfacial surface energies.

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