Substrate Rigidity Controls Activation and Durotaxis in Pancreatic Stellate Cells

Abstract 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 fibroti...

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Autores principales:	Dariusz Lachowski, Ernesto Cortes, Daniel Pink, Antonios Chronopoulos, Saadia A. Karim, Jennifer P. Morton, Armando E. del Río Hernández
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/e193b1e2c92148c1a09cd72152baee26
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spelling	oai:doaj.org-article:e193b1e2c92148c1a09cd72152baee262021-12-02T12:32:52ZSubstrate Rigidity Controls Activation and Durotaxis in Pancreatic Stellate Cells10.1038/s41598-017-02689-x2045-2322https://doaj.org/article/e193b1e2c92148c1a09cd72152baee262017-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-02689-xhttps://doaj.org/toc/2045-2322Abstract 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.Dariusz LachowskiErnesto CortesDaniel PinkAntonios ChronopoulosSaadia A. KarimJennifer P. MortonArmando E. del Río HernándezNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-12 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Dariusz Lachowski Ernesto Cortes Daniel Pink Antonios Chronopoulos Saadia A. Karim Jennifer P. Morton Armando E. del Río Hernández Substrate Rigidity Controls Activation and Durotaxis in Pancreatic Stellate Cells
description	Abstract 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.
format	article
author	Dariusz Lachowski Ernesto Cortes Daniel Pink Antonios Chronopoulos Saadia A. Karim Jennifer P. Morton Armando E. del Río Hernández
author_facet	Dariusz Lachowski Ernesto Cortes Daniel Pink Antonios Chronopoulos Saadia A. Karim Jennifer P. Morton Armando E. del Río Hernández
author_sort	Dariusz Lachowski
title	Substrate Rigidity Controls Activation and Durotaxis in Pancreatic Stellate Cells
title_short	Substrate Rigidity Controls Activation and Durotaxis in Pancreatic Stellate Cells
title_full	Substrate Rigidity Controls Activation and Durotaxis in Pancreatic Stellate Cells
title_fullStr	Substrate Rigidity Controls Activation and Durotaxis in Pancreatic Stellate Cells
title_full_unstemmed	Substrate Rigidity Controls Activation and Durotaxis in Pancreatic Stellate Cells
title_sort	substrate rigidity controls activation and durotaxis in pancreatic stellate cells
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/e193b1e2c92148c1a09cd72152baee26
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Substrate Rigidity Controls Activation and Durotaxis in Pancreatic Stellate Cells

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