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Cell-cell adhesion and 3D matrix confinement determine jamming transitions in breast cancer invasion.

ABSTRACT: Plasticity of cancer invasion and metastasis depends on the ability of cancer cells to switch between collective and single-cell dissemination, controlled by cadherin-mediated cell-cell junctions. In clinical samples, E-cadherin-expressing and -deficient tumours both invade collectively and metastasize equally, implicating additional mechanisms controlling cell-cell cooperation and individualization. Here, using spatially defined organotypic culture, intravital microscopy of mammary tumours in mice and in silico modelling, we identify cell density regulation by three-dimensional tissue boundaries to physically control collective movement irrespective of the composition and stability of cell-cell junctions. Deregulation of adherens junctions by downregulation of E-cadherin and p120-catenin resulted in a transition from coordinated to uncoordinated collective movement along extracellular boundaries, whereas single-cell escape depended on locally free tissue space. These results indicate that cadherins and extracellular matrix confinement cooperate to determine unjamming transitions and stepwise epithelial fluidization towards, ultimately, cell individualization.

SUBMITTER: Ilina O

PROVIDER: S-EPMC7502685 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Cell-cell adhesion and 3D matrix confinement determine jamming transitions in breast cancer invasion.

Ilina Olga O Gritsenko Pavlo G PG Syga Simon S Lippoldt Jürgen J La Porta Caterina A M CAM Chepizhko Oleksandr O Grosser Steffen S Vullings Manon M Bakker Gert-Jan GJ Starruß Jörn J Bult Peter P Zapperi Stefano S Käs Josef A JA Deutsch Andreas A Friedl Peter P

Nature cell biology 20200824 9

Plasticity of cancer invasion and metastasis depends on the ability of cancer cells to switch between collective and single-cell dissemination, controlled by cadherin-mediated cell-cell junctions. In clinical samples, E-cadherin-expressing and -deficient tumours both invade collectively and metastasize equally, implicating additional mechanisms controlling cell-cell cooperation and individualization. Here, using spatially defined organotypic culture, intravital microscopy of mammary tumours in m ...[more]

PMID: 32839548

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Project description:The progression of cancer in the breast involves multiple reciprocal interactions between malignantly transformed epithelia, surrounding untransformed but affected stromal cells, and the extracellular matrix (ECM) that is remodeled during the process. A quantitative understanding of the relative contribution of such interactions to phenotypes associated with cancer cells can be arrived at through the construction of increasingly complex experimental and computational models. Herein, we introduce a multiscale three-dimensional (3D) organo- and pathotypic experimental assay that approximates, to an unprecedented extent, the histopathological complexity of a tumor disseminating into its surrounding stromal milieu via both bulk and solitary motility dynamics. End point and time-lapse microscopic observations of this assay allow us to study the earliest steps of cancer invasion as well as the dynamical interactions between the epithelial and stromal compartments. We then simulate our experimental observations using the modeling environment Compucell3D that is based on the Glazier-Graner-Hogeweg model. The computational model, which comprises adhesion between cancer cells and the matrices, cell proliferation and apoptosis, and matrix remodeling through reaction-diffusion-based morphogen dynamics, is first trained to phenocopy controls run with the experimental model, wherein one or the other matrices have been removed. The trained computational model successfully predicts phenotypes of the experimental counterparts that are subjected to pharmacological treatments (inhibition of N-linked glycosylation and matrix metalloproteinase activity) and scaffold modulation (alteration of collagen density). Further parametric exploration-based simulations suggest that specific permissive regimes of cell-cell and cell-matrix adhesions, operating in the context of a reaction-diffusion-regulated ECM dynamics, promote multiscale invasion of breast cancer cells and determine the extent to which the latter migrate through their surrounding stroma.

Dataset Information

Cell-cell adhesion and 3D matrix confinement determine jamming transitions in breast cancer invasion.

Publications

Cell-cell adhesion and 3D matrix confinement determine jamming transitions in breast cancer invasion.

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