Interplay of adherens junctions and matrix proteolysis determines the invasive pattern and growth of squamous cell carcinoma
Cancers, such as squamous cell carcinoma, frequently invade as multicellular units. However, these invading units can be organised in a variety of ways, ranging from thin discontinuous strands to thick ‘pushing’ collectives. Here we employ an integrated experimental and computational approach to ide...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2023-03-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/76520 |
| _version_ | 1811155675330379776 |
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| author | Takuya Kato Robert P Jenkins Stefanie Derzsi Melda Tozluoglu Antonio Rullan Steven Hooper Raphaël AG Chaleil Holly Joyce Xiao Fu Selvam Thavaraj Paul A Bates Erik Sahai |
| author_facet | Takuya Kato Robert P Jenkins Stefanie Derzsi Melda Tozluoglu Antonio Rullan Steven Hooper Raphaël AG Chaleil Holly Joyce Xiao Fu Selvam Thavaraj Paul A Bates Erik Sahai |
| author_sort | Takuya Kato |
| collection | DOAJ |
| description | Cancers, such as squamous cell carcinoma, frequently invade as multicellular units. However, these invading units can be organised in a variety of ways, ranging from thin discontinuous strands to thick ‘pushing’ collectives. Here we employ an integrated experimental and computational approach to identify the factors that determine the mode of collective cancer cell invasion. We find that matrix proteolysis is linked to the formation of wide strands but has little effect on the maximum extent of invasion. Cell-cell junctions also favour wide strands, but our analysis also reveals a requirement for cell-cell junctions for efficient invasion in response to uniform directional cues. Unexpectedly, the ability to generate wide invasive strands is coupled to the ability to grow effectively when surrounded by extracellular matrix in three-dimensional assays. Combinatorial perturbation of both matrix proteolysis and cell-cell adhesion demonstrates that the most aggressive cancer behaviour, both in terms of invasion and growth, is achieved at high levels of cell-cell adhesion and high levels of proteolysis. Contrary to expectation, cells with canonical mesenchymal traits – no cell-cell junctions and high proteolysis – exhibit reduced growth and lymph node metastasis. Thus, we conclude that the ability of squamous cell carcinoma cells to invade effectively is also linked to their ability to generate space for proliferation in confined contexts. These data provide an explanation for the apparent advantage of retaining cell-cell junctions in squamous cell carcinomas. |
| first_indexed | 2024-04-10T04:37:19Z |
| format | Article |
| id | doaj.art-4f843d4c51a4448cb745c3c57242e71f |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-10T04:37:19Z |
| publishDate | 2023-03-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-4f843d4c51a4448cb745c3c57242e71f2023-03-09T13:27:51ZengeLife Sciences Publications LtdeLife2050-084X2023-03-011210.7554/eLife.76520Interplay of adherens junctions and matrix proteolysis determines the invasive pattern and growth of squamous cell carcinomaTakuya Kato0https://orcid.org/0000-0002-4972-657XRobert P Jenkins1https://orcid.org/0000-0002-6186-7746Stefanie Derzsi2Melda Tozluoglu3Antonio Rullan4Steven Hooper5Raphaël AG Chaleil6Holly Joyce7Xiao Fu8Selvam Thavaraj9https://orcid.org/0000-0001-5720-7422Paul A Bates10https://orcid.org/0000-0003-0621-0925Erik Sahai11https://orcid.org/0000-0002-3932-5086Tumour Cell Biology Laboratory, The Francis Crick Institute, London, United Kingdom; Department of Pathology, Kitasato University, Sagamihara, JapanTumour Cell Biology Laboratory, The Francis Crick Institute, London, United KingdomTumour Cell Biology Laboratory, The Francis Crick Institute, London, United Kingdom; Hoffman La-Roche, Basel, SwitzerlandBiomolecular Modelling Laboratory, The Francis Crick Institute, London, United KingdomTumour Cell Biology Laboratory, The Francis Crick Institute, London, United Kingdom; Institute of Cancer Research, London, United KingdomTumour Cell Biology Laboratory, The Francis Crick Institute, London, United KingdomBiomolecular Modelling Laboratory, The Francis Crick Institute, London, United KingdomTumour Cell Biology Laboratory, The Francis Crick Institute, London, United KingdomTumour Cell Biology Laboratory, The Francis Crick Institute, London, United Kingdom; Biomolecular Modelling Laboratory, The Francis Crick Institute, London, United KingdomCentre for Oral, Clinical and Translational Sciences, King's College London, London, United KingdomBiomolecular Modelling Laboratory, The Francis Crick Institute, London, United KingdomTumour Cell Biology Laboratory, The Francis Crick Institute, London, United KingdomCancers, such as squamous cell carcinoma, frequently invade as multicellular units. However, these invading units can be organised in a variety of ways, ranging from thin discontinuous strands to thick ‘pushing’ collectives. Here we employ an integrated experimental and computational approach to identify the factors that determine the mode of collective cancer cell invasion. We find that matrix proteolysis is linked to the formation of wide strands but has little effect on the maximum extent of invasion. Cell-cell junctions also favour wide strands, but our analysis also reveals a requirement for cell-cell junctions for efficient invasion in response to uniform directional cues. Unexpectedly, the ability to generate wide invasive strands is coupled to the ability to grow effectively when surrounded by extracellular matrix in three-dimensional assays. Combinatorial perturbation of both matrix proteolysis and cell-cell adhesion demonstrates that the most aggressive cancer behaviour, both in terms of invasion and growth, is achieved at high levels of cell-cell adhesion and high levels of proteolysis. Contrary to expectation, cells with canonical mesenchymal traits – no cell-cell junctions and high proteolysis – exhibit reduced growth and lymph node metastasis. Thus, we conclude that the ability of squamous cell carcinoma cells to invade effectively is also linked to their ability to generate space for proliferation in confined contexts. These data provide an explanation for the apparent advantage of retaining cell-cell junctions in squamous cell carcinomas.https://elifesciences.org/articles/76520invasive patterntumour microenvironmentcellular mechanismscomputational modelling |
| spellingShingle | Takuya Kato Robert P Jenkins Stefanie Derzsi Melda Tozluoglu Antonio Rullan Steven Hooper Raphaël AG Chaleil Holly Joyce Xiao Fu Selvam Thavaraj Paul A Bates Erik Sahai Interplay of adherens junctions and matrix proteolysis determines the invasive pattern and growth of squamous cell carcinoma eLife invasive pattern tumour microenvironment cellular mechanisms computational modelling |
| title | Interplay of adherens junctions and matrix proteolysis determines the invasive pattern and growth of squamous cell carcinoma |
| title_full | Interplay of adherens junctions and matrix proteolysis determines the invasive pattern and growth of squamous cell carcinoma |
| title_fullStr | Interplay of adherens junctions and matrix proteolysis determines the invasive pattern and growth of squamous cell carcinoma |
| title_full_unstemmed | Interplay of adherens junctions and matrix proteolysis determines the invasive pattern and growth of squamous cell carcinoma |
| title_short | Interplay of adherens junctions and matrix proteolysis determines the invasive pattern and growth of squamous cell carcinoma |
| title_sort | interplay of adherens junctions and matrix proteolysis determines the invasive pattern and growth of squamous cell carcinoma |
| topic | invasive pattern tumour microenvironment cellular mechanisms computational modelling |
| url | https://elifesciences.org/articles/76520 |
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