The ECM and tissue architecture are major determinants of early invasion mediated by E-cadherin dysfunction
Abstract Germline mutations of E-cadherin cause Hereditary Diffuse Gastric Cancer (HDGC), a highly invasive cancer syndrome characterised by the occurrence of diffuse-type gastric carcinoma and lobular breast cancer. In this disease, E-cadherin-defective cells are detected invading the adjacent stro...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2023-11-01
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| Series: | Communications Biology |
| Online Access: | https://doi.org/10.1038/s42003-023-05482-x |
| _version_ | 1797630052151590912 |
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| author | Soraia Melo Pilar Guerrero Maurício Moreira Soares José Rafael Bordin Fátima Carneiro Patrícia Carneiro Maria Beatriz Dias João Carvalho Joana Figueiredo Raquel Seruca Rui D. M. Travasso |
| author_facet | Soraia Melo Pilar Guerrero Maurício Moreira Soares José Rafael Bordin Fátima Carneiro Patrícia Carneiro Maria Beatriz Dias João Carvalho Joana Figueiredo Raquel Seruca Rui D. M. Travasso |
| author_sort | Soraia Melo |
| collection | DOAJ |
| description | Abstract Germline mutations of E-cadherin cause Hereditary Diffuse Gastric Cancer (HDGC), a highly invasive cancer syndrome characterised by the occurrence of diffuse-type gastric carcinoma and lobular breast cancer. In this disease, E-cadherin-defective cells are detected invading the adjacent stroma since very early stages. Although E-cadherin loss is well established as a triggering event, other determinants of the invasive process persist largely unknown. Herein, we develop an experimental strategy that comprises in vitro extrusion assays using E-cadherin mutants associated to HDGC, as well as mathematical models epitomising epithelial dynamics and its interaction with the extracellular matrix (ECM). In vitro, we verify that E-cadherin dysfunctional cells detach from the epithelial monolayer and extrude basally into the ECM. Through phase-field modelling we demonstrate that, aside from loss of cell-cell adhesion, increased ECM attachment further raises basal extrusion efficiency. Importantly, by combining phase-field and vertex model simulations, we show that the cylindrical structure of gastric glands strongly promotes the cell’s invasive ability. Moreover, we validate our findings using a dissipative particle dynamics simulation of epithelial extrusion. Overall, we provide the first evidence that cancer cell invasion is the outcome of defective cell-cell linkages, abnormal interplay with the ECM, and a favourable 3D tissue structure. |
| first_indexed | 2024-03-11T11:02:36Z |
| format | Article |
| id | doaj.art-cf546053fed94afea7fc40377b3b573e |
| institution | Directory Open Access Journal |
| issn | 2399-3642 |
| language | English |
| last_indexed | 2024-03-11T11:02:36Z |
| publishDate | 2023-11-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Communications Biology |
| spelling | doaj.art-cf546053fed94afea7fc40377b3b573e2023-11-12T12:27:13ZengNature PortfolioCommunications Biology2399-36422023-11-016111110.1038/s42003-023-05482-xThe ECM and tissue architecture are major determinants of early invasion mediated by E-cadherin dysfunctionSoraia Melo0Pilar Guerrero1Maurício Moreira Soares2José Rafael Bordin3Fátima Carneiro4Patrícia Carneiro5Maria Beatriz Dias6João Carvalho7Joana Figueiredo8Raquel Seruca9Rui D. M. Travasso10i3S – Instituto de Investigação e Inovação em Saúde, Universidade do PortoDepartamento de Matemáticas and Grupo Interdisciplinar de Sistemas Complejos (GISC), Universidad Carlos III de MadridOslo Center for Biostatistics and Epidemiology, Faculty of Medicine, University of OsloDepartment of Physics, Institute of Physics and Mathematics, Federal University of Pelotasi3S – Instituto de Investigação e Inovação em Saúde, Universidade do Portoi3S – Instituto de Investigação e Inovação em Saúde, Universidade do PortoCISUC, Department of Informatics Engineering, University of CoimbraCFisUC, Department of Physics, University of Coimbrai3S – Instituto de Investigação e Inovação em Saúde, Universidade do Portoi3S – Instituto de Investigação e Inovação em Saúde, Universidade do PortoCFisUC, Department of Physics, University of CoimbraAbstract Germline mutations of E-cadherin cause Hereditary Diffuse Gastric Cancer (HDGC), a highly invasive cancer syndrome characterised by the occurrence of diffuse-type gastric carcinoma and lobular breast cancer. In this disease, E-cadherin-defective cells are detected invading the adjacent stroma since very early stages. Although E-cadherin loss is well established as a triggering event, other determinants of the invasive process persist largely unknown. Herein, we develop an experimental strategy that comprises in vitro extrusion assays using E-cadherin mutants associated to HDGC, as well as mathematical models epitomising epithelial dynamics and its interaction with the extracellular matrix (ECM). In vitro, we verify that E-cadherin dysfunctional cells detach from the epithelial monolayer and extrude basally into the ECM. Through phase-field modelling we demonstrate that, aside from loss of cell-cell adhesion, increased ECM attachment further raises basal extrusion efficiency. Importantly, by combining phase-field and vertex model simulations, we show that the cylindrical structure of gastric glands strongly promotes the cell’s invasive ability. Moreover, we validate our findings using a dissipative particle dynamics simulation of epithelial extrusion. Overall, we provide the first evidence that cancer cell invasion is the outcome of defective cell-cell linkages, abnormal interplay with the ECM, and a favourable 3D tissue structure.https://doi.org/10.1038/s42003-023-05482-x |
| spellingShingle | Soraia Melo Pilar Guerrero Maurício Moreira Soares José Rafael Bordin Fátima Carneiro Patrícia Carneiro Maria Beatriz Dias João Carvalho Joana Figueiredo Raquel Seruca Rui D. M. Travasso The ECM and tissue architecture are major determinants of early invasion mediated by E-cadherin dysfunction Communications Biology |
| title | The ECM and tissue architecture are major determinants of early invasion mediated by E-cadherin dysfunction |
| title_full | The ECM and tissue architecture are major determinants of early invasion mediated by E-cadherin dysfunction |
| title_fullStr | The ECM and tissue architecture are major determinants of early invasion mediated by E-cadherin dysfunction |
| title_full_unstemmed | The ECM and tissue architecture are major determinants of early invasion mediated by E-cadherin dysfunction |
| title_short | The ECM and tissue architecture are major determinants of early invasion mediated by E-cadherin dysfunction |
| title_sort | ecm and tissue architecture are major determinants of early invasion mediated by e cadherin dysfunction |
| url | https://doi.org/10.1038/s42003-023-05482-x |
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