title: Extracellular matrix stiffness and composition jointly regulate the induction of malignant phenotypes in mammary epithelium.
abstract: 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.
authors.affiliation: 1] School of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts 02138, USA [2] Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, Massachusetts 02115, USA [3] Department of Mechanical Engineering, Stanford University, Stanford, California 94305, USA.
authors.forename: Ovijit
authors.initials: O
authors.lastname: Chaudhuri
authors.affiliation: 1] School of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts 02138, USA [2] Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, Massachusetts 02115, USA [3] Harvard-MIT Division of Health Sciences and Technology, Cambridge, Massachusetts 02139, USA.
authors.forename: Sandeep T
authors.initials: ST
authors.lastname: Koshy
authors.affiliation: 1] School of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts 02138, USA [2] Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, Massachusetts 02115, USA [3] Institute of Molecular Pathology and Immunology, Instituto de Engenharia Biomédica, and Faculty of Medicine of the University of Porto, Porto 4150-180, Portugal.
authors.forename: Cristiana
authors.initials: C
authors.lastname: Branco da Cunha
authors.affiliation: 1] School of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts 02138, USA [2] Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, Massachusetts 02115, USA.
authors.forename: Jae-Won
authors.initials: JW
authors.lastname: Shin
authors.affiliation: 1] School of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts 02138, USA [2] Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, Massachusetts 02115, USA.
authors.forename: Catia S
authors.initials: CS
authors.lastname: Verbeke
authors.affiliation: Department of Pathology, Stanford University Medical Center, Stanford, California 94305, USA.
authors.forename: Kimberly H
authors.initials: KH
authors.lastname: Allison
authors.affiliation: 1] School of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts 02138, USA [2] Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, Massachusetts 02115, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Mooney
mesh_terms: D000464:Alginates / Q000378:metabolism; D001485:Basement Membrane / Q000502:physiology; D001672:Biocompatible Materials; D055592:Biophysical Phenomena; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000378:metabolism* / Q000473:pathology*; D004848:Epithelium / Q000473:pathology / Q000503:physiopathology; D005109:Extracellular Matrix / Q000502:physiology*; D005260:Female; D020723:Glucuronic Acid / Q000378:metabolism; D022002:Hemidesmosomes / Q000502:physiology; D006603:Hexuronic Acids / Q000378:metabolism; D006801:Humans; D039161:Integrin alpha6beta4 / Q000378:metabolism; D008024:Ligands; D042361:Mammary Glands, Human / Q000473:pathology* / Q000503:physiopathology*; D040542:Mechanotransduction, Cellular / Q000502:physiology; D008954:Models, Biological; D010641:Phenotype; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D015398:Signal Transduction; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
chemical_list: D000464:Alginates; D001672:Biocompatible Materials; D006603:Hexuronic Acids; D039161:Integrin alpha6beta4; D008024:Ligands; C107953:RAC1 protein, human; D020723:Glucuronic Acid; D019869:Phosphatidylinositol 3-Kinases; D020830:rac1 GTP-Binding Protein