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Substrate rigidity controls activation and durotaxis in pancreatic stellate cells

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Title: Substrate rigidity controls activation and durotaxis in pancreatic stellate cells
Authors: Lachowski, D
Cortes, E
Pink, D
Chronopoulos, A
Karim, SA
Morton, JP
Hernandez, AEDR
Item Type: Journal Article
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.
Issue Date: 31-May-2017
Date of Acceptance: 18-Apr-2017
URI: http://hdl.handle.net/10044/1/48582
DOI: https://dx.doi.org/10.1038/s41598-017-02689-x
ISSN: 2045-2322
Publisher: Nature Publishing Group
Journal / Book Title: Scientific Reports
Volume: 7
Copyright Statement: © The Author(s) 2017. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Cre- ative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not per- mitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
Sponsor/Funder: Commission of the European Communities
Funder's Grant Number: 282051
Keywords: Science & Technology
Multidisciplinary Sciences
Science & Technology - Other Topics
FOCAL ADHESIONS
CANCER CELLS
DESMOPLASTIC REACTION
FIBROBLAST DUROTAXIS
MATRIX STIFFNESS
CARCINOMA-CELLS
STARRING ROLE
FIBROSIS
MIGRATION
MICROENVIRONMENT
Publication Status: Published
Article Number: ARTN 2506
Appears in Collections:Faculty of Engineering
Bioengineering



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