title: A complex secretory program orchestrated by the inflammasome controls paracrine senescence.
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.
authors.affiliation: Cell Proliferation Group, MRC Clinical Sciences Centre, Imperial College London, Hammersmith Campus, London W12 0NN, UK.
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Acosta
authors.forename: Ana
authors.initials: A
authors.lastname: Banito
authors.forename: Torsten
authors.initials: T
authors.lastname: Wuestefeld
authors.forename: Athena
authors.initials: A
authors.lastname: Georgilis
authors.forename: Peggy
authors.initials: P
authors.lastname: Janich
authors.forename: Jennifer P
authors.initials: JP
authors.lastname: Morton
authors.forename: Dimitris
authors.initials: D
authors.lastname: Athineos
authors.forename: Tae-Won
authors.initials: TW
authors.lastname: Kang
authors.forename: Felix
authors.initials: F
authors.lastname: Lasitschka
authors.forename: Mindaugas
authors.initials: M
authors.lastname: Andrulis
authors.forename: Gloria
authors.initials: G
authors.lastname: Pascual
authors.forename: Kelly J
authors.initials: KJ
authors.lastname: Morris
authors.forename: Sadaf
authors.initials: S
authors.lastname: Khan
authors.forename: Hong
authors.initials: H
authors.lastname: Jin
authors.forename: Gopuraja
authors.initials: G
authors.lastname: Dharmalingam
authors.forename: Ambrosius P
authors.initials: AP
authors.lastname: Snijders
authors.forename: Thomas
authors.initials: T
authors.lastname: Carroll
authors.forename: David
authors.initials: D
authors.lastname: Capper
authors.forename: Catrin
authors.initials: C
authors.lastname: Pritchard
authors.forename: Gareth J
authors.initials: GJ
authors.lastname: Inman
authors.forename: Thomas
authors.initials: T
authors.lastname: Longerich
authors.forename: Owen J
authors.initials: OJ
authors.lastname: Sansom
authors.forename: Salvador Aznar
authors.initials: SA
authors.lastname: Benitah
authors.forename: Lars
authors.initials: L
authors.lastname: Zender
authors.forename: Jesús
authors.initials: J
authors.lastname: Gil
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000502:physiology*; D003110:Colonic Neoplasms / Q000503:physiopathology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D058847:Inflammasomes / Q000378:metabolism*; D007375:Interleukin-1 / Q000378:metabolism; D051379:Mice; D023421:Models, Animal; D019899:Paracrine Communication / Q000502:physiology; D011485:Protein Binding; D015398:Signal Transduction; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: D058847:Inflammasomes; D007375:Interleukin-1; D053773:Transforming Growth Factor beta1