ATRA mechanically reprograms pancreatic stellate cells to suppress matrix remodelling and inhibit cancer cell invasion

Antonios Chronopoulos, Benjamin Robinson, Muge Sarper, Ernesto Cortes, Vera Auernheimer, Dariusz Lachowski, Simon Attwood, Rebeca García, Saba Ghassemi, Ben Fabry and Armando del Río Hernández ()
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Antonios Chronopoulos: Cellular and Molecular Biomechanics Laboratory, Imperial College London
Benjamin Robinson: Cellular and Molecular Biomechanics Laboratory, Imperial College London
Muge Sarper: Cellular and Molecular Biomechanics Laboratory, Imperial College London
Ernesto Cortes: Cellular and Molecular Biomechanics Laboratory, Imperial College London
Vera Auernheimer: Biophysics Group, University of Erlangen-Nuremberg
Dariusz Lachowski: Cellular and Molecular Biomechanics Laboratory, Imperial College London
Simon Attwood: Cellular and Molecular Biomechanics Laboratory, Imperial College London
Rebeca García: Cellular and Molecular Biomechanics Laboratory, Imperial College London
Saba Ghassemi: University of Pennsylvania School of Medicine
Ben Fabry: Biophysics Group, University of Erlangen-Nuremberg
Armando del Río Hernández: Cellular and Molecular Biomechanics Laboratory, Imperial College London

Nature Communications, 2016, vol. 7, issue 1, 1-12

Abstract: 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: 2016
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DOI: 10.1038/ncomms12630

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