Portal de investigação
The ECM and tissue architecture are major determinants of early invasion mediated by E-cadherin dysfunction
Data de publicação:
Autores da FMUP
Participantes de fora da FMUP
- Melo, S
- Guerrero, P
- Soares, MM
- Bordin, JR
- Carneiro, P
- Dias, MB
- Carvalho, J
- Seruca, R
- Travasso, DM
Unidades de investigação
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. The use of mathematical modelling and in vitro assays shows that loss of cell-cell adhesion, increased ECM attachment and tissue architecture promote invasion in a model of hereditary diffuse gastric cancer.
Dados da publicação
- ISSN/ISSNe:
- 2399-3642, 2399-3642
- Tipo:
- Article
- Páginas:
- -
- Link para outro recurso:
- www.scopus.com
Communications Biology Springer Nature
Citações Recebidas na Scopus: 1
Documentos
- Não há documentos
Filiações
Keywords
- DIFFUSE GASTRIC-CANCER; MEMBRANE TENSION; CELL-ADHESION; GERMLINE MUTATIONS; CDH1; GASTRECTOMY; MIGRATION; CARRIERS; MODEL
Financiamento
Proyectos asociados
The role of hepatocyte apoptosis markers in predicting the histological and serological activity in steatohepatitis
Investigador Principal: Maria de Fátima Machado Henriques Carneiro
Estudo Clínico Académico . 2021
Gastric Cancer Morphological, Immunophenotypic and molecular heterogeneity
Investigador Principal: Maria de Fátima Machado Henriques Carneiro
Estudo Clínico Académico . 2020
Citar a publicação
Melo S,Guerrero P,Soares MM,Bordin JR,Carneiro F,Carneiro P,Dias MB,Carvalho J,Figueiredo J,Seruca R,Travasso DM. The ECM and tissue architecture are major determinants of early invasion mediated by E-cadherin dysfunction. Commun. Biolog. 2023. 6. (1):1132. IF:5,900. (1).
