ATRA mechanically reprograms pancreatic stellate cells to suppress matrix remodelling and inhibit cancer cell invasion
File(s)
Published version
Accepted version
Author(s)
Type
Journal Article
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with a dismal survival rate. Persistent activation of pancreatic stellate cells (PSCs) can perturb the biomechanical homoeostasis of the tumour microenvironment to favour cancer cell invasion. Here we report that ATRA, an active metabolite of vitamin A, restores mechanical quiescence in PSCs via a mechanism involving a retinoic acid receptor beta (RAR-β)-dependent downregulation of actomyosin (MLC-2) contractility. We show that ATRA reduces the ability of PSCs to generate high traction forces and adapt to extracellular mechanical cues (mechanosensing), as well as suppresses force-mediated extracellular matrix remodelling to inhibit local cancer cell invasion in 3D organotypic models. Our findings implicate a RAR-β/MLC-2 pathway in peritumoural stromal remodelling and mechanosensory-driven activation of PSCs, and further suggest that mechanical reprogramming of PSCs with retinoic acid derivatives might be a viable alternative to stromal ablation strategies for the treatment of PDAC.
Date Issued
2016-09-07
Date Acceptance
2016-07-18
Citation
Nature Communications, 2016, 7 (1), pp.1-12
ISSN
2041-1723
Publisher
Nature Research
Start Page
1
End Page
12
Journal / Book Title
Nature Communications
Volume
7
Issue
1
Copyright Statement
This work is licensed under a Creative Commons Attribution 4.0
International License. The images or other third party material in this
article are included in the article’s Creative Commons license, unless indicated otherwise
in the credit line; if the material is not included under the Creative Commons license,
users will need to obtain permission from the license holder to reproduce the material.
To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
© The Author(s) 2016
International License. The images or other third party material in this
article are included in the article’s Creative Commons license, unless indicated otherwise
in the credit line; if the material is not included under the Creative Commons license,
users will need to obtain permission from the license holder to reproduce the material.
To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
© The Author(s) 2016
License URL
Sponsor
Commission of the European Communities
Identifier
https://www.nature.com/articles/ncomms12630
Grant Number
282051
Subjects
Science & Technology
Multidisciplinary Sciences
Science & Technology - Other Topics
TRANS-RETINOIC ACID
DUCTAL ADENOCARCINOMA
EXTRACELLULAR-MATRIX
TUMOR PROGRESSION
CARCINOMA-CELLS
ACTIVATION
FIBROBLASTS
FIBROSIS
STRESS
STROMA
Carcinoma, Pancreatic Ductal
Cell Adhesion
Cell Proliferation
Focal Adhesions
Humans
Mechanotransduction, Cellular
Neoplasm Invasiveness
Pancreatic Stellate Cells
Tretinoin
Tumor Microenvironment
Focal Adhesions
Humans
Carcinoma, Pancreatic Ductal
Neoplasm Invasiveness
Tretinoin
Cell Adhesion
Mechanotransduction, Cellular
Cell Proliferation
Pancreatic Stellate Cells
Tumor Microenvironment
Publication Status
Published online
Article Number
12630
Date Publish Online
2016-09-07