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      A complex secretory program orchestrated by the inflammasome controls paracrine senescence

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          Abstract

          Oncogene-induced senescence (OIS) is crucial for tumour suppression. Senescent cells implement a complex pro-inflammatory response termed the senescence-associated secretory phenotype (SASP). The SASP reinforces senescence, activates immune surveillance and paradoxically also has pro-tumourigenic properties. Here, we present evidence that the SASP can also induce “paracrine senescence” in normal cells both in culture and in human and mouse models of OIS in vivo. Coupling quantitative proteomics with small molecule screens, we identified multiple SASP components mediating paracrine senescence, including TGFβ family ligands, VEGF, CCL2 and CCL20. Amongst them, TGFβ ligands play a major role by regulating p15 INK4b and p21 CIP1. Expression of the SASP is controlled by inflammasome-mediated IL-1 signalling. The inflammasome and IL-1 signalling are activated in senescent cells and IL-1α expression can reproduce SASP activation, resulting in senescence. Our results demonstrate that the SASP can cause paracrine senescence and impact on tumour suppression and senescence in vivo.

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          Most cited references 53

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          The inflammasomes.

          Inflammasomes are molecular platforms activated upon cellular infection or stress that trigger the maturation of proinflammatory cytokines such as interleukin-1beta to engage innate immune defenses. Strong associations between dysregulated inflammasome activity and human heritable and acquired inflammatory diseases highlight the importance this pathway in tailoring immune responses. Here, we comprehensively review mechanisms directing normal inflammasome function and its dysregulation in disease. Agonists and activation mechanisms of the NLRP1, NLRP3, IPAF, and AIM2 inflammasomes are discussed. Regulatory mechanisms that potentiate or limit inflammasome activation are examined, as well as emerging links between the inflammasome and pyroptosis and autophagy. 2010 Elsevier Inc. All rights reserved.
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            Cellular senescence: when bad things happen to good cells.

            Cells continually experience stress and damage from exogenous and endogenous sources, and their responses range from complete recovery to cell death. Proliferating cells can initiate an additional response by adopting a state of permanent cell-cycle arrest that is termed cellular senescence. Understanding the causes and consequences of cellular senescence has provided novel insights into how cells react to stress, especially genotoxic stress, and how this cellular response can affect complex organismal processes such as the development of cancer and ageing.
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              TGFbeta in Cancer.

              The transforming growth factor beta (TGFbeta) signaling pathway is a key player in metazoan biology, and its misregulation can result in tumor development. The regulatory cytokine TGFbeta exerts tumor-suppressive effects that cancer cells must elude for malignant evolution. Yet, paradoxically, TGFbeta also modulates processes such as cell invasion, immune regulation, and microenvironment modification that cancer cells may exploit to their advantage. Consequently, the output of a TGFbeta response is highly contextual throughout development, across different tissues, and also in cancer. The mechanistic basis and clinical relevance of TGFbeta's role in cancer is becoming increasingly clear, paving the way for a better understanding of the complexity and therapeutic potential of this pathway.
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                Author and article information

                Journal
                100890575
                21417
                Nat Cell Biol
                Nat. Cell Biol.
                Nature cell biology
                1465-7392
                1476-4679
                27 June 2013
                16 June 2013
                August 2013
                01 February 2014
                : 15
                : 8
                : 978-990
                Affiliations
                [1 ]Cell Proliferation Group, MRC Clinical Sciences Centre, Imperial College London, Hammersmith Campus, London W12 0NN, UK
                [2 ]Epigenetics Section, MRC Clinical Sciences Centre, Imperial College London, Hammersmith Campus, London W12 0NN, UK
                [3 ]Division of Translational Gastrointestinal Oncology, Dept. of Internal Medicine I, Eberhard Karls University Tübingen, 72076 Tübingen, Germany
                [4 ]Center for Genomic Regulation and UPF, Barcelona, Spain
                [5 ]The Beatson Institute for Cancer Research, Glasgow, United Kingdom
                [6 ]Institute of Pathology, University of Heidelberg, and Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany
                [7 ]Department of Biochemistry, University of Leicester, Leicester LE1 9HN, United Kingdom
                [8 ]Proteomics Facility; MRC Clinical Sciences Centre, Imperial College London, Hammersmith Campus, London W12 0NN, UK
                [9 ]Department of Neuropathology, University of Heidelberg, and Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany
                [10 ]Medical Research Institute, University of Dundee, Dundee, United Kingdom
                Author notes
                [* ] Corresponding author: jesus.gil@ 123456csc.mrc.ac.uk Phone: +44 20 8383 8263
                [+]

                Equal contribution.

                [#]

                Current address: Edinburgh Cancer Research UK Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Crewe Road South, Edinburgh EH4 2XR, UK

                Article
                EMS53737
                10.1038/ncb2784
                3732483
                23770676

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                Categories
                Article

                Cell biology

                inflammasome, paracrine, il-1α, secretome, sasp, senescence, tgfβ

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