Cell–cell adhesion and 3D matrix confinement determine jamming transitions in breast cancer invasion
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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.
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Efforts have been made to design anisotropic matrix structures in CoC devices, particularly collagen type I, to recapitulate in vivo-like aligned collagen-rich ECM interacting with invasive tumors, using engineered, directional force-derived, or cell-derived approaches.
“More recently, however, efforts have been made to design anisotropic matrix structures (including in CoC devices) in particular, but not exclusively, collagen type I [24], with the aim of recapitulating in vivo-like aligned collagen-rich ECM interacting with invasive tumors [25] by using (i) engineered, (ii) directional force-derived, or (iii) cell-derived approaches (Figure 2A-C and Table 1).”
From Cancer-on-chip models for metastasis: importance of the tumor microenvironment (2024) · cites this paper as [25]
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- Authors
- Ilina, O., Gritsenko, P. G., Syga, S., Lippoldt, J., La Porta, C. A. M., Chepizhko, O., Grosser, S., Vullings, M., Bakker, G.-J., Starruß, J., Bult, P., Zapperi, S., Käs, J. A., Deutsch, A., & Friedl, P.
- Affiliations
- Radboud University Medical Center (NL)
- Center for Information Services and High Performance Computing (DE)
- Leipzig University (DE)
- Universität Innsbruck (AT)
- University of Milan (IT)
- The University of Texas MD Anderson Cancer Center (US)
- Corresponding author
- Friedl, Peter
- ORCID
- Venue
- Nature Cell Biology
- Published
- 2020-08-24
- Volume
- 22
- Issue
- 9
- Pages
- 1103-1115
- ISSN
- 1465-7392 (ISSN-L)
- 1476-4679
- PMC
- PMC7502685
- OpenAlex
- W3080611254
- Cited by
- 375
- References
- 67
- Citations by year
- 2026: 45 · 2025: 69 · 2024: 60 · 2023: 61 · 2022: 53 · 2021: 74 · 2020: 10 · 2012: 2
- FWCI
- 24.69
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Cell Biology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, other-oa)
- Radboud Repository (Radboud University) (submittedVersion)
- Funders
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek (918.11.626)
- National Cancer Institute (U54CA210184, P30CA016672)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular Mechanics and Interactions
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Health Sciences › Medicine › Immunology and Allergy › Cell Adhesion Molecules Research
- Keywords
- cell-cell adhesion, E-cadherin, p120 catenin, adherens junctions, collective cell migration, breast cancer invasion, metastasis, tissue boundaries, cell density regulation, unjamming transition, organotypic culture, intravital microscopy, in silico modeling
- MeSH terms
- Animals, Breast Neoplasms, Cell Adhesion, Cell Line, Female, Humans, Intercellular Junctions, Mice, Inbred BALB C, Neoplasm Invasiveness, Down-Regulation, Gene Expression Regulation, Neoplastic, Adherens Junctions, Cell Line, Tumor, HEK293 Cells, MCF-7 Cells
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