Rapid disorganization of mechanically interacting systems of mammary acini

Significance Tissue mechanics are important in differentiation and development but also in diseases like breast cancer. Most breast cancers start in mammary acini, which are basic anatomical units of the mammary gland. We found in a model system that mammary acini can coordinate their disorganization toward a malignant phenotype through long-range mechanical interactions. When two or more contractile acini are sufficiently close together, they can interact via collagen lines that form between them due to acinar contractility and the nonlinearity of collagen mechanics. Disorganization of interacting acini is more probable, rapid, and extensive than that of noninteracting acini. The results may help to better understand how extrinsic factors such as tissue architecture and mechanics contribute to tumor initiation and progression. Cells and multicellular structures can mechanically align and concentrate fibers in their ECM environment and can sense and respond to mechanical cues by differentiating, branching, or disorganizing. Here we show that mammary acini with compromised structural integrity can interconnect by forming long collagen lines. These collagen lines then coordinate and accelerate transition to an invasive phenotype. Interacting acini begin to disorganize within 12.5 ± 4.7 h in a spatially coordinated manner, whereas acini that do not interact mechanically with other acini disorganize more slowly (in 21.8 ± 4.1 h) and to a lesser extent (P < 0.0001). When the directed mechanical connections between acini were cut with a laser, the acini reverted to a slowly disorganizing phenotype. When acini were fully mechanically isolated from other acini and also from the bulk gel by box-cuts with a side length <900 μm, transition to an invasive phenotype was blocked in 20 of 20 experiments, regardless of waiting time. Thus, pairs or groups of mammary acini can interact mechanically over long distances through the collagen matrix, and these directed mechanical interactions facilitate transition to an invasive phenotype.