3 août 2013 6 03 /08 /août /2013 08:19
A complex secretory program orchestrated by the inflammasome controls paracrine senescence Juan Carlos Acosta, Ana Banito, Torsten Wuestefeld, Athena Georgilis, Peggy Janich, Jennifer P. Morton, Dimitris Athineos, Tae-Won Kang, Felix Lasitschka, Mindaugas Andrulis, Gloria Pascual, Kelly J. Morris, Sadaf Khan, Hong Jin, Gopuraja Dharmalingam, Ambrosius P. Snijders, Thomas Carroll, David Capper, Catrin Pritchard, Gareth J. Inman, Thomas Longerich, Owen J. Sansom, Salvador Aznar Benitah, Lars Zender & Jesús Gil AffiliationsCorresponding author Nature Cell Biology 15, 978–990 (2013) doi:10.1038/ncb2784 Received 01 October 2012 Accepted 13 May 2013 Published online 16 June 2013 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. Copley et al. Transmitting senescence to the cell neighbourhood pp887 - 889 Matthew Hoare and Masashi Narita Senescence, a cell-autonomous tumour suppressor mechanism, also has pro-tumorigenic effects on neighbouring pre-malignant cells through the senescence-associated secretory phenotype (SASP). The SASP is now shown to be regulated by inflammasomes and to induce paracrine senescence in healthy cells, indicating that senescence may also represent a non-cell-autonomous tumour suppressor mechanism linked to innate immunity.