![]() ![]() The contractile myofibroblast-like phenotype is a general hallmark feature of cancer-associated fibroblasts (CAFs) 13. In pancreatic cancer, PSCs transition from a quiescent, lipid-vitamin-A storing phenotype to an activated, myofibroblast-like phenotype that is accompanied by changes in their cytoskeletal and contractile activity, migratory capacity, extracellular matrix (ECM) synthesis and acquisition of an expansive secretome 12. Recently, this desmoplastic reaction has been the focus of several studies that have emphasized the complex nature of the stromal components and their contribution to disease progression 5, 6, 7, 8, 9, 10, 11. PDAC is characterized by a strong desmoplastic reaction or stromal fibrosis, which is driven by pancreatic stellate cells (PSCs) and is believed to create a unique microenvironment that regulates tumour growth, metastasis and chemoresistance 2, 3, 4. Pancreatic ductal adenocarcinoma (PDAC) is an extremely aggressive cancer with a dismal 5-year survival rate of 4% and a median survival of 6 months despite advances in conventional therapies targeting cancer cells 1. 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. 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. 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. ![]() Persistent activation of pancreatic stellate cells (PSCs) can perturb the biomechanical homoeostasis of the tumour microenvironment to favour cancer cell invasion. Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with a dismal survival rate. ![]()
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