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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 references34

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          Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas.

          Although cancer arises from a combination of mutations in oncogenes and tumour suppressor genes, the extent to which tumour suppressor gene loss is required for maintaining established tumours is poorly understood. p53 is an important tumour suppressor that acts to restrict proliferation in response to DNA damage or deregulation of mitogenic oncogenes, by leading to the induction of various cell cycle checkpoints, apoptosis or cellular senescence. Consequently, p53 mutations increase cell proliferation and survival, and in some settings promote genomic instability and resistance to certain chemotherapies. To determine the consequences of reactivating the p53 pathway in tumours, we used RNA interference (RNAi) to conditionally regulate endogenous p53 expression in a mosaic mouse model of liver carcinoma. We show that even brief reactivation of endogenous p53 in p53-deficient tumours can produce complete tumour regressions. The primary response to p53 was not apoptosis, but instead involved the induction of a cellular senescence program that was associated with differentiation and the upregulation of inflammatory cytokines. This program, although producing only cell cycle arrest in vitro, also triggered an innate immune response that targeted the tumour cells in vivo, thereby contributing to tumour clearance. Our study indicates that p53 loss can be required for the maintenance of aggressive carcinomas, and illustrates how the cellular senescence program can act together with the innate immune system to potently limit tumour growth.
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            Chemokine signaling via the CXCR2 receptor reinforces senescence.

            Cells enter senescence, a state of stable proliferative arrest, in response to a variety of cellular stresses, including telomere erosion, DNA damage, and oncogenic signaling, which acts as a barrier against malignant transformation in vivo. To identify genes controlling senescence, we conducted an unbiased screen for small hairpin RNAs that extend the life span of primary human fibroblasts. Here, we report that knocking down the chemokine receptor CXCR2 (IL8RB) alleviates both replicative and oncogene-induced senescence (OIS) and diminishes the DNA-damage response. Conversely, ectopic expression of CXCR2 results in premature senescence via a p53-dependent mechanism. Cells undergoing OIS secrete multiple CXCR2-binding chemokines in a program that is regulated by the NF-kappaB and C/EBPbeta transcription factors and coordinately induce CXCR2 expression. CXCR2 upregulation is also observed in preneoplastic lesions in vivo. These results suggest that senescent cells activate a self-amplifying secretory network in which CXCR2-binding chemokines reinforce growth arrest.
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              Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse.

              To evaluate the role of oncogenic RAS mutations in pancreatic tumorigenesis, we directed endogenous expression of KRAS(G12D) to progenitor cells of the mouse pancreas. We find that physiological levels of Kras(G12D) induce ductal lesions that recapitulate the full spectrum of human pancreatic intraepithelial neoplasias (PanINs), putative precursors to invasive pancreatic cancer. The PanINs are highly proliferative, show evidence of histological progression, and activate signaling pathways normally quiescent in ductal epithelium, suggesting potential therapeutic and chemopreventive targets for the cognate human condition. At low frequency, these lesions also progress spontaneously to invasive and metastatic adenocarcinomas, establishing PanINs as definitive precursors to the invasive disease. Finally, mice with PanINs have an identifiable serum proteomic signature, suggesting a means of detecting the preinvasive state in patients.
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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
                c3641de4-caee-4799-9d09-aecdbeebaa5f

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                Categories
                Article

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

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