title: NOTCH1 mediates a switch between two distinct secretomes during senescence.
abstract: Senescence, a persistent form of cell-cycle arrest, is often associated with a diverse secretome, which provides complex functionality for senescent cells within the tissue microenvironment. We show that oncogene-induced senescence is accompanied by a dynamic fluctuation of NOTCH1 activity, which drives a TGF-β-rich secretome, while suppressing the senescence-associated pro-inflammatory secretome through inhibition of C/EBPβ. NOTCH1 and NOTCH1-driven TGF-β contribute to 'lateral induction of senescence' through a juxtacrine NOTCH-JAG1 pathway. In addition, NOTCH1 inhibition during senescence facilitates upregulation of pro-inflammatory cytokines, promoting lymphocyte recruitment and senescence surveillance in vivo. As enforced activation of NOTCH1 signalling confers a near mutually exclusive secretory profile compared with typical senescence, our data collectively indicate that the dynamic alteration of NOTCH1 activity during senescence dictates a functional balance between these two distinct secretomes: one representing TGF-β and the other pro-inflammatory cytokines, highlighting that NOTCH1 is a temporospatial controller of secretome composition.
authors.affiliation: University of Cambridge, Cancer Research UK Cambridge Institute, Robinson Way, Cambridge CB2 0RE, UK.|University of Cambridge, Department of Medicine, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
authors.forename: Matthew
authors.initials: M
authors.lastname: Hoare
authors.affiliation: University of Cambridge, Cancer Research UK Cambridge Institute, Robinson Way, Cambridge CB2 0RE, UK.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Ito
authors.affiliation: Division of Translational Gastrointestinal Oncology, Department of Internal Medicine I, University Hospital Tuebingen, Otfried-Mueller-Strasse 12, 72076 Tuebingen, Germany.|Translational Gastrointestinal Oncology Group within the German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Tae-Won
authors.initials: TW
authors.lastname: Kang
authors.affiliation: University of Cambridge, Department of Medicine, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.|University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Cambridge CB2 0XY, UK.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Weekes
authors.affiliation: University of Cambridge, Department of Medicine, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.|University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Cambridge CB2 0XY, UK.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Matheson
authors.affiliation: National Institute for Health Research Birmingham Liver Biomedical Research Unit and Centre for Liver Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TT, UK.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Patten
authors.affiliation: National Institute for Health Research Birmingham Liver Biomedical Research Unit and Centre for Liver Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TT, UK.
authors.forename: Shishir
authors.initials: S
authors.lastname: Shetty
authors.affiliation: University of Cambridge, Cancer Research UK Cambridge Institute, Robinson Way, Cambridge CB2 0RE, UK.
authors.forename: Aled J
authors.initials: AJ
authors.lastname: Parry
authors.affiliation: University of Cambridge, Cancer Research UK Cambridge Institute, Robinson Way, Cambridge CB2 0RE, UK.
authors.forename: Suraj
authors.initials: S
authors.lastname: Menon
authors.affiliation: University of Cambridge, Cancer Research UK Cambridge Institute, Robinson Way, Cambridge CB2 0RE, UK.
authors.forename: Rafik
authors.initials: R
authors.lastname: Salama
authors.affiliation: University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Cambridge CB2 0XY, UK.
authors.forename: Robin
authors.initials: R
authors.lastname: Antrobus
authors.affiliation: University of Cambridge, Cancer Research UK Cambridge Institute, Robinson Way, Cambridge CB2 0RE, UK.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Tomimatsu
authors.affiliation: University of Cambridge, Cancer Research UK Cambridge Institute, Robinson Way, Cambridge CB2 0RE, UK.
authors.forename: William
authors.initials: W
authors.lastname: Howat
authors.affiliation: University of Cambridge, Department of Medicine, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.|University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Cambridge CB2 0XY, UK.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Lehner
authors.affiliation: Division of Translational Gastrointestinal Oncology, Department of Internal Medicine I, University Hospital Tuebingen, Otfried-Mueller-Strasse 12, 72076 Tuebingen, Germany.|Translational Gastrointestinal Oncology Group within the German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Lars
authors.initials: L
authors.lastname: Zender
authors.affiliation: University of Cambridge, Cancer Research UK Cambridge Institute, Robinson Way, Cambridge CB2 0RE, UK.
authors.forename: Masashi
authors.initials: M
authors.lastname: Narita
mesh_terms: D000818:Animals; D059447:Cell Cycle Checkpoints / Q000502:physiology*; D045744:Cell Line, Tumor; D016922:Cellular Senescence; D006801:Humans; D008822:Mice, Transgenic; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: C497761:NOTCH1 protein, human; C497762:Notch1 protein, mouse; D051881:Receptor, Notch1; D016212:Transforming Growth Factor beta