Dynamic extracellular matrix stiffening induces a phenotypic transformation and a migratory shift in epithelial cells

Abstract Soft tissue tumors, including breast cancer, become stiffer throughout disease progression. This increase in stiffness has been shown to correlate to malignant phenotype and epithelial-to-mesenchymal transition (EMT) in vitro. Unlike current models, utilizing static increases in matrix stif...

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Bibliographic Details
Published in:Integrative biology (Cambridge) 2020-06, Vol.12 (6), p.161-174
Main Authors: Allen, Shane C, Widman, Jessica A, Datta, Anisha, Suggs, Laura J
Format: Article
Language:English
Subjects:
1-Phosphatidylinositol 3-kinase
Alginates
Alginic acid
Animal models
Breast cancer
Cell migration
Clusters
Cytology
Epithelial cells
Epithelium
Extracellular matrix
Genetic transformation
Hydrogels
Markers
Mesenchyme
Metastases
Metastasis
Morphology
Phenotypes
Soft tissues
Stiffening
Stiffness
Tumors
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Summary:Abstract Soft tissue tumors, including breast cancer, become stiffer throughout disease progression. This increase in stiffness has been shown to correlate to malignant phenotype and epithelial-to-mesenchymal transition (EMT) in vitro. Unlike current models, utilizing static increases in matrix stiffness, our group has previously created a system that allows for dynamic stiffening of an alginate–matrigel composite hydrogel to mirror the native dynamic process. Here, we utilize this system to evaluate the role of matrix stiffness on EMT and metastasis both in vitro and in vivo. Epithelial cells were seen to lose normal morphology and become protrusive and migratory after stiffening. This shift corresponded to a loss of epithelial markers and gain of mesenchymal markers in both the cell clusters and migrated cells. Furthermore, stiffening in a murine model reduced tumor burden and increased migratory behavior prior to tumor formation. Inhibition of FAK and PI3K in vitro abrogated the morphologic and migratory transformation of epithelial cell clusters. This work demonstrates the key role extracellular matrix stiffening has in tumor progression through integrin signaling and, in particular, its ability to drive EMT-related changes and metastasis.
ISSN:1757-9708
1757-9694
1757-9708
DOI:10.1093/intbio/zyaa012