title: ATRA modulates mechanical activation of TGF-β by pancreatic stellate cells.
abstract: The hallmark of pancreatic ductal adenocarcinoma (PDAC) is abundant desmoplasia, which is orchestrated by pancreatic stellate cells (PSCs) and accounts for the majority of the stroma surrounding the tumour. Healthy PSCs are quiescent, but upon activation during disease progression, they adopt a myofibroblast-contractile phenotype and secrete and concomitantly reorganise the stiff extracellular matrix (ECM). Transforming growth factor β (TGF-β) is a potent activator of PSCs, and its activation requires spatiotemporal organisation of cellular and extracellular cues to liberate it from an inactive complex with latent TGF-β binding protein (LTBP). Here we study the mechanical activation of TGF-β by PSCs in vitro by investigating LTBP-1 organisation with fibrillar fibronectin and show that all trans-retinoic acid (ATRA), which induces PSC quiescence, down-regulates the ability of PSCs to mechanically organise LTBP-1 and activate TGF-β through a mechanism involving myosin II dependent contractility. Therefore, ATRA inhibits the ability of PSCs to mechanically release active TGF-β, which might otherwise act in an autocrine manner to sustain PSCs in an active state and a tumour-favouring stiff microenvironment.
authors.affiliation: Cellular and Molecular Biomechanics Laboratory, Department of Bioengineering, Faculty of Engineering, Imperial College London, South Kensington Campus, London SW7 2AZ, United Kingdom.
authors.forename: Muge
authors.initials: M
authors.lastname: Sarper
authors.affiliation: Cellular and Molecular Biomechanics Laboratory, Department of Bioengineering, Faculty of Engineering, Imperial College London, South Kensington Campus, London SW7 2AZ, United Kingdom.
authors.forename: Ernesto
authors.initials: E
authors.lastname: Cortes
authors.affiliation: Cellular and Molecular Biomechanics Laboratory, Department of Bioengineering, Faculty of Engineering, Imperial College London, South Kensington Campus, London SW7 2AZ, United Kingdom.
authors.forename: Tyler J
authors.initials: TJ
authors.lastname: Lieberthal
authors.affiliation: Cellular and Molecular Biomechanics Laboratory, Department of Bioengineering, Faculty of Engineering, Imperial College London, South Kensington Campus, London SW7 2AZ, United Kingdom.
authors.forename: Armando
authors.initials: A
authors.lastname: Del Río Hernández
mesh_terms: D000205:Actomyosin / Q000737:chemistry; D017398:Alternative Splicing; D021441:Carcinoma, Pancreatic Ductal / Q000378:metabolism; D003599:Cytoskeleton / Q000737:chemistry; D018450:Disease Progression; D005353:Fibronectins / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism; D053779:Latent TGF-beta Binding Proteins / Q000378:metabolism*; D058628:Myofibroblasts / Q000378:metabolism; D024462:Myosin Type II / Q000378:metabolism; D010190:Pancreatic Neoplasms; D058954:Pancreatic Stellate Cells / Q000378:metabolism*; D010641:Phenotype; D013314:Stress, Mechanical; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D014212:Tretinoin / Q000378:metabolism*; D059016:Tumor Microenvironment
chemical_list: D005353:Fibronectins; D019012:Integrin beta1; C509032:LTBP1 protein, human; D053779:Latent TGF-beta Binding Proteins; C508960:TGFB1 protein, human; D053773:Transforming Growth Factor beta1; D014212:Tretinoin; D000205:Actomyosin; D024462:Myosin Type II