Invasion in breast cancer organoids as a mechano-biological instability

Cancer invasion is a complex and diverse process that tightly couples cellular responses, physico-chemical properties of the extracellular matrix, and interaction between cells and the matrix, notably through adhesion molecules called integrins. It is known that the ability of cells to sense the mechanical propertis of the matrix and react to these mechanical signals is crucial during invasion, but why some cells adopt an invasive phenotype or the physical mechanism by which the cell mass invades the matrix are not well understood. To address this question in a controlled and accessible system, we focus on in vitro breast cancer organoids embedded in collagen matrices. Somewhat surprisingly, observations show that these organoids invade the matrix by pulling on it, which necessarily means that cells must locally degrade collagen. Based on this observation, we develop a theory that explains invasion as a self-organized pattern resulting from a positive feedback loop between matrix strain-stiffening, cellular mechanosensing and enhanced local degradation. The predictions of this theory agree with observations in breast cancer organoids and with experiments specifically designed to test these predictions,