ATRA mechanically reprograms pancreatic stellate cells to suppress matrix remodelling and inhibit cancer cell invasion.
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.
Cellular and Molecular Biomechanics Laboratory, Department of Bioengineering, Imperial College London, London SW7 2AZ, UK.
Antonios
A
Chronopoulos
Cellular and Molecular Biomechanics Laboratory, Department of Bioengineering, Imperial College London, London SW7 2AZ, UK.
Benjamin
B
Robinson
Cellular and Molecular Biomechanics Laboratory, Department of Bioengineering, Imperial College London, London SW7 2AZ, UK.
Muge
M
Sarper
Cellular and Molecular Biomechanics Laboratory, Department of Bioengineering, Imperial College London, London SW7 2AZ, UK.
Ernesto
E
Cortes
Department of Physics, Biophysics Group, University of Erlangen-Nuremberg, Erlangen 91054, Germany.
Vera
V
Auernheimer
Cellular and Molecular Biomechanics Laboratory, Department of Bioengineering, Imperial College London, London SW7 2AZ, UK.
Dariusz
D
Lachowski
Cellular and Molecular Biomechanics Laboratory, Department of Bioengineering, Imperial College London, London SW7 2AZ, UK.
Simon
S
Attwood
Cellular and Molecular Biomechanics Laboratory, Department of Bioengineering, Imperial College London, London SW7 2AZ, UK.
Rebeca
R
García
Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
Saba
S
Ghassemi
Department of Physics, Biophysics Group, University of Erlangen-Nuremberg, Erlangen 91054, Germany.
Ben
B
Fabry
Cellular and Molecular Biomechanics Laboratory, Department of Bioengineering, Imperial College London, London SW7 2AZ, UK.
Armando
A
Del Río Hernández
D021441:Carcinoma, Pancreatic Ductal; D002448:Cell Adhesion; D049109:Cell Proliferation; D022001:Focal Adhesions; D006801:Humans; D040542:Mechanotransduction, Cellular / Q000187:drug effects; D009361:Neoplasm Invasiveness / Q000517:prevention & control*; D058954:Pancreatic Stellate Cells / Q000187:drug effects* / Q000502:physiology; D014212:Tretinoin / Q000494:pharmacology*; D059016:Tumor Microenvironment
D014212:Tretinoin