Extracellular matrix stiffness and composition jointly regulate the induction of malignant phenotypes in mammary epithelium

In vitro models of normal mammary epithelium have correlated increased extracellular matrix (ECM) stiffness with malignant phenotypes. However, the role of increased stiffness in this transformation remains unclear because of difficulties in controlling ECM stiffness, composition and architecture in...

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Bibliographic Details
Published in:Nature materials 2014-10, Vol.13 (10), p.970-978
Main Authors: Chaudhuri, Ovijit, Koshy, Sandeep T, Branco da Cunha, Cristiana, Shin, Jae-Won, Verbeke, Catia S, Allison, Kimberly H, Mooney, David J
Format: Article
Language:English
Subjects:
Alginates - metabolism
Architecture
Basement Membrane - physiology
Basements
Biocompatible Materials
Biophysical Phenomena
Cell Line
Cell Transformation, Neoplastic - metabolism
Cell Transformation, Neoplastic - pathology
Cells
Cellular biology
Electrochemical machining
Epithelium
Epithelium - pathology
Epithelium - physiopathology
Extracellular Matrix - physiology
Female
Genotype & phenotype
Glucuronic Acid - metabolism
Hemidesmosomes - physiology
Hexuronic Acids - metabolism
Humans
Integrin alpha6beta4 - metabolism
Interpenetrating networks
Ligands
Mammary Glands, Human - pathology
Mammary Glands, Human - physiopathology
Matrix
Mechanotransduction, Cellular - physiology
Membranes
Models, Biological
Phenotype
Phosphatidylinositol 3-Kinases - metabolism
rac1 GTP-Binding Protein - metabolism
Signal Transduction
Stiffness
Transformations
Tumors
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Summary:In vitro models of normal mammary epithelium have correlated increased extracellular matrix (ECM) stiffness with malignant phenotypes. However, the role of increased stiffness in this transformation remains unclear because of difficulties in controlling ECM stiffness, composition and architecture independently. Here we demonstrate that interpenetrating networks of reconstituted basement membrane matrix and alginate can be used to modulate ECM stiffness independently of composition and architecture. We find that, in normal mammary epithelial cells, increasing ECM stiffness alone induces malignant phenotypes but that the effect is completely abrogated when accompanied by an increase in basement-membrane ligands. We also find that the combination of stiffness and composition is sensed through β4 integrin, Rac1, and the PI3K pathway, and suggest a mechanism in which an increase in ECM stiffness, without an increase in basement membrane ligands, prevents normal α6β4 integrin clustering into hemidesmosomes.
ISSN:1476-1122
1476-4660
DOI:10.1038/nmat4009