Notch Signaling Mediates Secondary Senescence

Oncogene-induced senescence (OIS) is a tumor suppressive response to oncogene activation that can be transmitted to neighboring cells through secreted factors of the senescence-associated secretory phenotype (SASP). Currently, primary and secondary senescent cells are not considered functionally dis...

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Published in:Cell reports (Cambridge) Vol. 27; no. 4; pp. 997 - 1007.e5
Main Authors: Teo, Yee Voan, Rattanavirotkul, Nattaphong, Olova, Nelly, Salzano, Angela, Quintanilla, Andrea, Tarrats, Nuria, Kiourtis, Christos, Müller, Miryam, Green, Anthony R., Adams, Peter D., Acosta, Juan-Carlos, Bird, Thomas G., Kirschner, Kristina, Neretti, Nicola, Chandra, Tamir
Format: Journal Article
Language:English
Published: United States Elsevier Inc 23.04.2019
Cell Press
Subjects:
Animals
bystander senescence
CEBPB
Cells, Cultured
Cellular Senescence
Humans
Mice, Inbred C57BL
Notch
oncogene induced senescence
Oncogenes - physiology
paracrine senescence
Receptors, Notch - metabolism
Receptors, Notch - physiology
secondary senescence
senescence
senescence associated secretory phenotype
Signal Transduction
Single-Cell Analysis
single-cell RNA sequencing
TGFB
Transcriptome
single-cell RNA sequencing
senescence
CEBPB
secondary senescence
senescence associated secretory phenotype
Notch
paracrine senescence
TGFB
oncogene induced senescence
bystander senescence
ISSN:2211-1247, 2211-1247
Online Access:Get full text
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Summary:Oncogene-induced senescence (OIS) is a tumor suppressive response to oncogene activation that can be transmitted to neighboring cells through secreted factors of the senescence-associated secretory phenotype (SASP). Currently, primary and secondary senescent cells are not considered functionally distinct endpoints. Using single-cell analysis, we observed two distinct transcriptional endpoints, a primary endpoint marked by Ras and a secondary endpoint marked by Notch activation. We find that secondary oncogene-induced senescence in vitro and in vivo requires Notch, rather than SASP alone, as previously thought. Moreover, Notch signaling weakens, but does not abolish, SASP in secondary senescence. Global transcriptomic differences, a blunted SASP response, and the induction of fibrillar collagens in secondary senescence point toward a functional diversification between secondary and primary senescence. [Display omitted] •Primary senescence and secondary senescence are distinct molecular endpoints•Secondary Ras-induced senescence has a composite SASP, Notch-induced signature•Notch signaling is an essential driver of secondary senescence•Notch blunts the senescence-associated secretory phenotype in secondary senescence Teo et al. found that secondary senescence in vitro and in vivo requires Notch, rather than SASP alone, as previously thought. The authors show that primary and secondary senescence are distinct molecular endpoints. A blunted secretory phenotype and the induction of fibrillar collagens in secondary senescence point toward functional diversification.
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These authors contributed equally
ISSN:2211-1247
2211-1247
DOI:10.1016/j.celrep.2019.03.104