Substrate Rigidity Controls Activation and Durotaxis in Pancreatic Stellate Cells

Pancreatic Ductal Adenocarcinoma (PDAC) is an aggressive malignancy characterised by the presence of extensive desmoplasia, thought to be responsible for the poor response of patients to systemic therapies. Pancreatic stellate cells (PSCs) are key mediators in the production of this fibrotic stroma,...

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Veröffentlicht in:Scientific reports Jg. 7; H. 1; S. 2506 - 12
Hauptverfasser: Lachowski, Dariusz, Cortes, Ernesto, Pink, Daniel, Chronopoulos, Antonios, Karim, Saadia A., P. Morton, Jennifer, del Río Hernández, Armando E.
Format: Journal Article
Sprache:Englisch
Veröffentlicht: London Nature Publishing Group UK 31.05.2017
Nature Publishing Group
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Adenocarcinoma
Adenocarcinoma - genetics
Adenocarcinoma - pathology
Carcinoma, Pancreatic Ductal - genetics
Carcinoma, Pancreatic Ductal - pathology
Cell Movement - genetics
Cell Proliferation - drug effects
Cell Proliferation - genetics
Cellular Reprogramming - genetics
Collagen - pharmacology
Disease Progression
Drug Combinations
Extracellular matrix
Fibrosis
Gene Expression Regulation, Neoplastic - genetics
Humanities and Social Sciences
Humans
Laminin - pharmacology
Lipids
Malignancy
Medical research
multidisciplinary
Pancreas
Pancreatic cancer
Pancreatic Stellate Cells - drug effects
Pancreatic Stellate Cells - pathology
Primary Cell Culture
Proteoglycans - pharmacology
Rigidity
Science
Science (multidisciplinary)
Stellate cells
Stroma
Substrate Specificity
Tumor Microenvironment - genetics
ISSN:2045-2322, 2045-2322
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Zusammenfassung:Pancreatic Ductal Adenocarcinoma (PDAC) is an aggressive malignancy characterised by the presence of extensive desmoplasia, thought to be responsible for the poor response of patients to systemic therapies. Pancreatic stellate cells (PSCs) are key mediators in the production of this fibrotic stroma, upon activation transitioning to a myofibroblast-like, high matrix secreting phenotype. Given their importance in disease progression, characterisation of PSC activation has been extensive, however one aspect that has been overlooked is the mechano-sensing properties of the cell. Here, through the use of a physiomimetic system that recapitulates the mechanical microenvironment found within healthy and fibrotic pancreas, we demonstrate that matrix stiffness regulates activation and mechanotaxis in PSCs. We show the ability of PSCs to undergo phenotypic transition solely as a result of changes in extracellular matrix stiffness, whilst observing the ability of PSCs to durotactically respond to stiffness variations within their local environment. Our findings implicate the mechanical microenvironment as a potent contributor to PDAC progression and survival via induction of PSC activation and fibrosis, suggesting that direct mechanical reprogramming of PSCs may be a viable alternative in the treatment of this lethal disease.
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ISSN:2045-2322
2045-2322
DOI:10.1038/s41598-017-02689-x