Plasticity of cancer invasion and metastasis depends on the ability of cancer cells to switch between collective and single cell dissemination, controlled by cadherinmediated cell-cell junctions. In clinical samples, E-cadherin expressing and deficient tumors both invade collectively and metastasize equally, implicating additional mechanisms controlling cell-cell cooperation and individualization. Using spatially defined organotypic culture, intravital microscopy of mammary tumors in mice and in silico modeling, we here identify cell density regulation by 3D tissue boundaries to physically control collective movement irrespective of the composition and stability of cell-cell junctions. Deregulation of adherens junctions, including E-cadherin and p120-catenin, resulted in a transition from coordinated to uncoordinated collective movement along extracellular boundaries, whereas singlecell escape depended on locally free tissue space. These data indicate that cadherins and ECM confinement cooperate to determine unjamming transitions towards step-wise epithelial fluidization and, ultimately, cell individualization.

Cancer cell invasion into healthy tissues develops preferentially along pre-existing tracks of least resistance, followed by secondary tissue remodelling and destruction. The tissue scaffolds supporting or preventing guidance of invasion vary in structure and molecular composition between organs. In the brain, the guidance is provided by myelinated axons, astrocyte processes, and blood vessels which are used as invasion routes by glioma cells. In the human breast, containing interstitial collagen-rich connective tissue, disseminating breast cancer cells preferentially invade along bundled collagen fibrils and the surface of adipocytes. In both invasion types, physical guidance prompted by interfaces and space is complemented by molecular guidance. Generic mechanisms shared by most, if not all, tissues include (i) guidance by integrins towards fibrillar interstitial collagen and/or laminins and type IV collagen in basement membranes decorating vessels and adipocytes, and, likely, CD44 engaging with hyaluronan; (ii) haptotactic guidance by chemokines and growth factors; and likely (iii) physical pushing mechanisms. Tissue-specific, resticted guidance cues include ECM proteins with restricted expression (tenascins, lecticans), cell-cell interfaces, and newly secreted matrix molecules decorating ECM fibres (laminin-332, thrombospondin-1, osteopontin, periostin). We here review physical and molecular guidance mechanisms in interstitial tissue and brain parenchyma and explore shared principles and organ-specific differences, and their implications for experimental model design and therapeutic targeting of tumour cell invasion.

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