Mechanical plasticity of the ECM directs invasive branching morphogenesis in human mammary gland organoids

Although branching morphogenesis is central for organogenesis in diverse organs, the underlying self-organizing principles have yet to be identified. Here, we show that invasive branching morphogenesis in human mammary organoids relies on an intricate tension-driven feedback mechanism, which is based on the nonlinear and plastic mechanical response of the surrounding collagen network. Specifically, we demonstrate that collective motion of cells within organoid branches generates tension that is strong enough to induce a plastic reorganization of the surrounding collagen network which results in the formation of mechanically stable collagen cages. Such matrix encasing in turn directs further tension generation, branch outgrowth and plastic deformation of the matrix. The identified mechanical feedback-loop sets a framework to understand how mechanical cues direct organogenesis.