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 L. Carroll,David Capper,Catrin Pritchard,Gareth J. Inman,Thomas Longerich,Owen J. Sansom,Salvador Aznar Benitah,Lars Zender,Jesús Gil +24 more
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TLDR
It is demonstrated that the SASP can cause paracrine senescence and impact on tumour suppression andSenescence in vivo and TGF-β ligands play a major role by regulating p15INK4b and p21CIP1.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 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.read more
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Length‐independent telomere damage drives post‐mitotic cardiomyocyte senescence
Rhys Anderson,Anthony B. Lagnado,Damien Maggiorani,Anna Walaszczyk,Emily Dookun,James Chapman,Jodie Birch,Hanna Salmonowicz,Mikolaj Ogrodnik,Diana Jurk,Diana Jurk,Carole J. Proctor,Clara Correia-Melo,Stella Victorelli,Edward Fielder,Rolando Berlinguer-Palmini,A Owens,Laura C. Greaves,Kathy L Kolsky,Angelo Parini,Victorine Douin-Echinard,Nathan K. LeBrasseur,Helen M. Arthur,Simon Tual-Chalot,Marissa J. Schafer,Carolyn M Roos,Jordan D. Miller,Neil Robertson,Jelena Mann,Peter D. Adams,Peter D. Adams,Tamara Tchkonia,James L. Kirkland,Jeanne Mialet-Perez,Gavin D. Richardson,João F. Passos,João F. Passos +36 more
TL;DR: A mechanism by which senescence can occur and contribute to age‐related myocardial dysfunction and in the wider setting to ageing in post‐mitotic tissues is described.
Journal ArticleDOI
Global Reorganization of the Nuclear Landscape in Senescent Cells
Tamir Chandra,Tamir Chandra,Philip Ewels,Stefan Schoenfelder,Mayra Furlan-Magaril,Steven W. Wingett,Kristina Kirschner,Jean-Yves Thuret,Simon Andrews,Peter Fraser,Wolf Reik,Wolf Reik +11 more
TL;DR: Comparison of embryonic stem cells, somatic cells, and senescent cells shows a unidirectional loss in local chromatin connectivity, suggesting that senescence is an endpoint of the continuous nuclear remodelling process during differentiation.
Journal ArticleDOI
Tumour-infiltrating Gr-1 + myeloid cells antagonize senescence in cancer
Diletta Di Mitri,Alberto Toso,Jingjing Chen,Manuela Sarti,Sandra Pinton,Tanja Rezzonico Jost,Rocco D'Antuono,Erica Montani,Ramón García-Escudero,Ilaria Guccini,Sabela Da Silva-Álvarez,Manuel Collado,Mario A. Eisenberger,Zhe Zhang,Carlo V. Catapano,Fabio Grassi,Andrea Alimonti +16 more
TL;DR: It is shown that at the onset of senescence, PTEN null prostate tumours in mice are massively infiltrated by a population of CD11b+Gr-1+ myeloid cells that protect a fraction of proliferating tumour cells from senescences, thus sustaining tumour growth.
Journal ArticleDOI
BRD4 Connects Enhancer Remodeling to Senescence Immune Surveillance
Nilgun Tasdemir,Ana Banito,Jae Seok Roe,Direna Alonso-Curbelo,Matthew Camiolo,Darjus F. Tschaharganeh,Chun-Hao Huang,Ozlem Aksoy,Jessica E. Bolden,Chi-Chao Chen,Myles Fennell,Vishal Thapar,Agustin Chicas,Christopher R. Vakoc,Scott W. Lowe,Scott W. Lowe +15 more
TL;DR: This study reveals how cells undergoing oncogene-induced senescence acquire a distinctive enhancer landscape that includes formation of super-enhancers adjacent to immune-modulatory genes required for paracrine immune activation.
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