Invited Talk

A mechano-biological feedback between cancer organoids and the ECM initiates and sustains collective invasion

Universitat Politecnica de Catalunya, Jordi Girona 1-3, Barcelona 08034, Spain

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During collective invasion, cohesive cellular strands extend into the matrix and reach distant locations. At invasive protrusions, so-called leader cells organize a region with focalized adhesion, force generation, matrix alignment and proteolysis, and mechanosensing. How some cells become leaders and initiate and sustain collective invasion is not well understood. To address this question, we study monoclonal MMTV-PyMT organoids embedded in collagen matrices, where all cells at the organoid-matrix interface have invasive potential. These organoids break symmetry to develop invasive patterns with multiple thick and cohesive protrusions. By following collagen and cellular dynamics during invasion, we identify a new feedback mechanisms involving fast and mechanosensitive matrix proteolysis and traction as well as the nonlinear mechanics of fibrous matrices. Using mathematical and computational modeling as well as experimental perturbations, we show that this mechanism can explain symmetry-breaking from spherical organoids, and the formation of patterns of persistent invasive collective protrusions.