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Abstract Background Tumour progression relies on the ability of cancer cells to penetrate and invade neighbouring tissues. E-cadherin loss is associated with increased cell invasion in gastric carcinoma, and germline mutations of the E-cadherin gene are causative of hereditary diffuse gastric cancer. Although E-cadherin dysfunction impacts cell–cell adhesion, cell dissemination also requires an imbalance of adhesion to the extracellular matrix (ECM). Methods To identify ECM components and receptors relevant for adhesion of E-cadherin dysfunctional cells, we implemented a novel ECM microarray platform coupled with molecular interaction networks. The functional role of putative candidates was determined by combining micropattern traction microscopy, protein modulation and in vivo approaches, as well as transcriptomic data of 262 gastric carcinoma samples, retrieved from the cancer genome atlas (TCGA). Results Here, we show that E-cadherin mutations induce an abnormal interplay of cells with specific components of the ECM, which encompasses increased traction forces and Integrin β1 activation. Integrin β1 synergizes with E-cadherin dysfunction, promoting cell scattering and invasion. The significance of the E-cadherin-Integrin β1 crosstalk was validated in Drosophila models and found to be consistent with evidence from human gastric carcinomas, where increased tumour grade and poor survival are associated with low E-cadherin and high Integrin β1 levels. Conclusions Integrin β1 is a key mediator of invasion in carcinomas with E-cadherin impairment and should be regarded as a biomarker of poor prognosis in gastric cancer.
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Durotaxis and extracellular matrix degradation promote the clustering of cancer cells
Early stages of metastasis depend on the collective behavior of cancer cells and their interaction with the extracellular matrix (ECM). Cancer cell clusters are known to exhibit higher metastatic potential than single cells. To explore clustering dynamics, we developed a calibrated computational model describing how motile cancer cells biochemically and biomechanically interact with the ECM during the initial invasion phase, including ECM degradation and mechanical remodeling. The model reveals that cluster formation time, size, and shape are influenced by ECM degradation rates and cellular compliance to external stresses (durotaxis). The results align with experimental observations, demonstrating distinct cell trajectories and cluster morphologies shaped by biomechanical parameters. The simulations provide valuable insights into cancer invasion dynamics and may suggest potential therapeutic strategies targeting early-stage invasive cells.
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- PAR ID:
- 10629865
- Publisher / Repository:
- Cell Press
- Date Published:
- Journal Name:
- iScience
- Volume:
- 28
- Issue:
- 3
- ISSN:
- 2589-0042
- Page Range / eLocation ID:
- 111883
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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- Free Publicly Accessible Full Text
-
Accepted Manuscript
- Journal Article:
- https://doi.org/10.1016/j.isci.2025.111883
