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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...

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Autores principales: Kato, Takuya, Jenkins, Robert P, Derzsi, Stefanie, Tozluoglu, Melda, Rullan, Antonio, Hooper, Steven, Chaleil, Raphaël AG, Joyce, Holly, Fu, Xiao, Thavaraj, Selvam, Bates, Paul A, Sahai, Erik
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9998089/
https://www.ncbi.nlm.nih.gov/pubmed/36892272
http://dx.doi.org/10.7554/eLife.76520
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author Kato, Takuya
Jenkins, Robert P
Derzsi, Stefanie
Tozluoglu, Melda
Rullan, Antonio
Hooper, Steven
Chaleil, Raphaël AG
Joyce, Holly
Fu, Xiao
Thavaraj, Selvam
Bates, Paul A
Sahai, Erik
author_facet Kato, Takuya
Jenkins, Robert P
Derzsi, Stefanie
Tozluoglu, Melda
Rullan, Antonio
Hooper, Steven
Chaleil, Raphaël AG
Joyce, Holly
Fu, Xiao
Thavaraj, Selvam
Bates, Paul A
Sahai, Erik
author_sort Kato, Takuya
collection PubMed
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.
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spelling pubmed-99980892023-03-10 Interplay of adherens junctions and matrix proteolysis determines the invasive pattern and growth of squamous cell carcinoma Kato, Takuya Jenkins, Robert P Derzsi, Stefanie Tozluoglu, Melda Rullan, Antonio Hooper, Steven Chaleil, Raphaël AG Joyce, Holly Fu, Xiao Thavaraj, Selvam Bates, Paul A Sahai, Erik eLife Cancer Biology 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. eLife Sciences Publications, Ltd 2023-03-09 /pmc/articles/PMC9998089/ /pubmed/36892272 http://dx.doi.org/10.7554/eLife.76520 Text en © 2023, Kato, Jenkins et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Cancer Biology
Kato, Takuya
Jenkins, Robert P
Derzsi, Stefanie
Tozluoglu, Melda
Rullan, Antonio
Hooper, Steven
Chaleil, Raphaël AG
Joyce, Holly
Fu, Xiao
Thavaraj, Selvam
Bates, Paul A
Sahai, Erik
Interplay of adherens junctions and matrix proteolysis determines the invasive pattern and growth of squamous cell carcinoma
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 Cancer Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9998089/
https://www.ncbi.nlm.nih.gov/pubmed/36892272
http://dx.doi.org/10.7554/eLife.76520
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