UCSF

Tissues in the body adopt regular structures that are actively maintained far from thermodynamic equilibrium and yet achieve a steady state. This control over cellular arrangements both ensures tissue function and protects against the spread of cancer cells in the mammary gland, where structural disruption marks the transition from in situ to invasive breast cancer and a major increase in patient risk. With a reconstituted human mammary organoid system derived from cultured primary cells, I model the steady-state structural distributions of tissues as a function of cellular mechanical properties, configurational entropies, and active fluctuations. These experimental results demonstrate a surprising concordance with equilibrium statistical mechanics. Activating one of the most commonly dysregulated breast cancer genes, \emph{PIK3CA}, causes decreased self-organization in mammary organoids via a change in cells’ mechanical properties. Making targeted changes to parameters of the tissue energy and active fluctuations with RNA interference and small molecule inhibition corrects organoid structure. This approach directly connects cell mechanics, cell dynamics, and tissue geometry to quantitative structural outcomes using a statistical mechanical framework. It also ties specific physical parameters to phenotypes of risk in breast cancer progression and lays the groundwork for future studies of the dynamics of tissue structure and state.