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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-tumorigenic 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 TGF-β family ligands, VEGF, CCL2 and CCL20. Amongst them, TGF-β ligands play a major role by regulating p15INK4b and p21CIP1. 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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Figure 1: Cells undergoing OIS can induce paracrine arrest of normal cells.
Figure 2: Paracrine senescence is a stable arrest mediated by soluble factors.
Figure 3: Paracrine senescence depends on the p16INK4a/Rb and p53/p21CIP1 tumour suppressor networks.
Figure 4: Multiple components of the SASP are involved in paracrine senescence.
Figure 5: A role for TGF-β signalling in mediating paracrine senescence.
Figure 6: The inflammasome regulates the senescence secretome.
Figure 7: IL-1 signalling regulates senescence.
Figure 8: Paracrine senescence is observed in mouse and human models of OIS in vivo.

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Acknowledgements

We are grateful to M. Stampfer (Lawrence Berkeley National Laboratory, USA), G. Núñez (University of Michigan, USA) and D. Escors (UCL, UK) for reagents and to T. Bird, S. Forbes, V. Episkopou, T. Rodrı´guez, P. Schirmacher, S. Parrinello, M. Narita, G. Peters and D. Beach for advice and critical reading of the manuscript. We also thank the tissue bank of the National Center for Tumour Diseases Heidelberg for providing colon tissues. Core support from the MRC and grants from MRCT, CRUK and the AICR financially supported the research in J.G’s laboratory. J.G. is also supported by the EMBO Young Investigator Programme.

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Acosta, J., Banito, A., Wuestefeld, T. et al. A complex secretory program orchestrated by the inflammasome controls paracrine senescence. Nat Cell Biol 15, 978–990 (2013). https://doi.org/10.1038/ncb2784

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