title: Induction of fibroblast senescence generates a non-fibrogenic myofibroblast phenotype that differentially impacts on cancer prognosis.
abstract: Cancer-associated fibroblasts (CAF) remain a poorly characterized, heterogeneous cell population. Here we characterized two previously described tumor-promoting CAF sub-types, smooth muscle actin (SMA)-positive myofibroblasts and senescent fibroblasts, identifying a novel link between the two. Analysis of CAF culturedex vivo, showed that senescent CAF are predominantly SMA-positive; this was confirmed by immunochemistry in head & neck (HNSCC) and esophageal (EAC) cancers.In vitro, we found that fibroblasts induced to senesce develop molecular, ultrastructural and contractile features typical of myofibroblasts and this is dependent on canonical TGF-β signaling. Similar to TGF-β1-generated myofibroblasts, these cells secrete soluble factors that promote tumor cell motility. However, RNA-sequencing revealed significant transcriptomic differences between the two SMA-positive CAF groups, particularly in genes associated with extracellular matrix (ECM) deposition and organization, which differentially promote tumor cell invasion. Notably, second harmonic generation imaging and bioinformatic analysis of SMA-positive human HNSCC and EAC showed that collagen fiber organization correlates with poor prognosis, indicating that heterogeneity within the SMA-positive CAF population differentially impacts on survival. These results show that non-fibrogenic, SMA-positive myofibroblasts can be directly generated through induction of fibroblast senescence and suggest that senescence and myofibroblast differentiation are closely linked processes.
authors.affiliation: Cancer Sciences Unit, Faculty of Medicine, University of Southampton, SO166YD, UK.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Mellone
authors.affiliation: Cancer Sciences Unit, Faculty of Medicine, University of Southampton, SO166YD, UK.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Hanley
authors.affiliation: Cancer Sciences Unit, Faculty of Medicine, University of Southampton, SO166YD, UK.
authors.forename: Steve
authors.initials: S
authors.lastname: Thirdborough
authors.affiliation: Cancer Sciences Unit, Faculty of Medicine, University of Southampton, SO166YD, UK.
authors.forename: Toby
authors.initials: T
authors.lastname: Mellows
authors.affiliation: Cancer Sciences Unit, Faculty of Medicine, University of Southampton, SO166YD, UK.
authors.forename: Edwin
authors.initials: E
authors.lastname: Garcia
authors.affiliation: Faculty of Medicine, University of Southampton, Southampton SO166YD, UK.
authors.forename: Jeongmin
authors.initials: J
authors.lastname: Woo
authors.affiliation: Cancer Sciences Unit, Faculty of Medicine, University of Southampton, SO166YD, UK.
authors.forename: Joanne
authors.initials: J
authors.lastname: Tod
authors.affiliation: Cancer Sciences Unit, Faculty of Medicine, University of Southampton, SO166YD, UK.
authors.forename: Steve
authors.initials: S
authors.lastname: Frampton
authors.affiliation: Cancer Sciences Unit, Faculty of Medicine, University of Southampton, SO166YD, UK.
authors.forename: Veronika
authors.initials: V
authors.lastname: Jenei
authors.affiliation: Cancer Sciences Unit, Faculty of Medicine, University of Southampton, SO166YD, UK.
authors.forename: Karwan A
authors.initials: KA
authors.lastname: Moutasim
authors.affiliation: Integrated Biosciences, School of Clinical Dentistry, University of Sheffield, Sheffield S102TA, UK.
authors.forename: Tasnuva D
authors.initials: TD
authors.lastname: Kabir
authors.affiliation: Queen Alexandra Hospital, Portsmouth Hospitals NHS Trust, Portsmouth PO63LY, UK.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Brennan
authors.affiliation: Cancer Sciences Unit, Faculty of Medicine, University of Southampton, SO166YD, UK.
authors.forename: Giulia
authors.initials: G
authors.lastname: Venturi
authors.affiliation: Cancer Sciences Unit, Faculty of Medicine, University of Southampton, SO166YD, UK.
authors.forename: Kirsty
authors.initials: K
authors.lastname: Ford
authors.affiliation: MRC Clinical Sciences Centre, Imperial College Faculty of Medicine, Hammersmith Hospital Campus, London W12, UK.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Herranz
authors.affiliation: Cancer Research Initiatives Foundation. Sime Darby Medical Centre, Subang Jaya, Selangor 47500, Malaysia.
authors.forename: Kue Peng
authors.initials: KP
authors.lastname: Lim
authors.affiliation: Cancer Sciences Unit, Faculty of Medicine, University of Southampton, SO166YD, UK.
authors.forename: James
authors.initials: J
authors.lastname: Clarke
authors.affiliation: Integrated Biosciences, School of Clinical Dentistry, University of Sheffield, Sheffield S102TA, UK.
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Lambert
authors.affiliation: Centre for Clinical and Diagnostic Oral Sciences, Institute of Dentistry, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London E12AD, UK.
authors.forename: Stephen S
authors.initials: SS
authors.lastname: Prime
authors.affiliation: Cancer Sciences Unit, Faculty of Medicine, University of Southampton, SO166YD, UK.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Underwood
authors.affiliation: La Jolla Institute for Allergy & Immunology, La Jolla, California 92037, USA.
authors.forename: Pandurangan
authors.initials: P
authors.lastname: Vijayanand
authors.affiliation: Laboratory for Optical and Computational Instrumentation (LOCI), Department of Biomedical Engineering, University of Madison, Wisconsin, WI 53706, USA.
authors.forename: Kevin W
authors.initials: KW
authors.lastname: Eliceiri
authors.affiliation: Faculty of Medicine, University of Southampton, Southampton SO166YD, UK.
authors.forename: Christopher
authors.initials: C
authors.lastname: Woelk
authors.affiliation: Cancer Sciences Unit, Faculty of Medicine, University of Southampton, SO166YD, UK.
authors.forename: Emma V
authors.initials: EV
authors.lastname: King
authors.affiliation: MRC Clinical Sciences Centre, Imperial College Faculty of Medicine, Hammersmith Hospital Campus, London W12, UK.
authors.forename: Jesus
authors.initials: J
authors.lastname: Gil
authors.affiliation: Cancer Sciences Unit, Faculty of Medicine, University of Southampton, SO166YD, UK.
authors.forename: Christian H
authors.initials: CH
authors.lastname: Ottensmeier
authors.affiliation: Cancer Sciences Unit, Faculty of Medicine, University of Southampton, SO166YD, UK.
authors.forename: Gareth J
authors.initials: GJ
authors.lastname: Thomas
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000502:physiology*; D005109:Extracellular Matrix / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D051379:Mice; D058628:Myofibroblasts / Q000378:metabolism / Q000473:pathology*; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology*; D010641:Phenotype; D011379:Prognosis; D015398:Signal Transduction / Q000502:physiology; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: D053773:Transforming Growth Factor beta1
keywords: collagen; extracellular matrix; myofibroblasts; senescence; senescent fibroblasts; tumor microenvironment