Cellular senescence is defined as a state of stable cell cycle exit in response to various stimuli, which include both cytotoxic stress and physiological cues. In addition to the core non-proliferative aspect, senescence is associated with diverse functionalities, which contribute to the role of senescence in a wide range of pathological and physiological processes. Such functionality is often mediated by the capability of senescent cells to communicate with their surroundings. Emerging evidence suggests that senescence is not a single entity, but a dynamic and heterogeneous collective phenotype. Understanding the diverse nature of senescence should provide insights into the complexity of tissue homeostasis and its disruption, such as in aging and tumorigenesis.
The essential feature of the autonomous aspect of senescence is stable proliferative arrest. This factor contributes to the tumor suppressive and pro-aging aspects of senescence, the latter in part mediated through limiting the replicative capacity of tissue stem cell compartments (Sharpless & DePinho (2007) Nat Rev Mol Cell Biol 8, 703–713).
However, senescence is not simply a static endpoint. In fact, senescent cells actively communicate with their neighboring cells within the tissue microenvironment (Pérez-Mancera PA
NOTCH proteins are conserved cell surface receptors, and NOTCH signaling has been implicated in diverse cellular processes, including embryonic development, cell fate and differentiation, as well as in tumorigenesis (Hoare M & Narita M (2018) Adv Exp Med Biol 1066, 299–318). In addition, emerging evidence indicates that NOTCH signaling is an important senescence effector (Ito Y
NOTCH signaling is also important for the spatial regulation of senescence. NOTCH signaling in mammals consists of five ligands and four receptors, all of which are cell surface proteins. Thus, NOTCH signaling is transmitted from signal-sending cells to signal-receiving cells through direct cell contact. This is an important aspect of its role in tissue patterning. In the developmental context, two modes of signal transmission have been proposed: lateral inhibition and lateral induction (Ito Y
Since NOTCH ligands are often upregulated in cancer, the implication of this NOTCH-mediated juxtacrine regulation of both the SASP and chromatin structure may not be limited to senescence. Indeed, cancer cell lines expressing a high level of endogenous JAG1 (a NOTCH ligand) can induce NIS in co-cultured fibroblasts (Diagram 1) (Parry AJ
This work was supported by the University of Cambridge, Cancer Research UK and Hutchison Whampoa. I thank Andrew Young for comments on this review. M.N. is supported by a Cancer Research UK Cambridge Institute core grant (C14303/A17197), a Cancer Research UK Early Detection Pump Priming award (C20/A20976), an MRC grant (MR/R010013/1), and Tokyo Tech World Research Hub Initiative (WRHI).
Hoare M et al., 2016, NOTCH1 mediates a switch between two distinct secretomes during senescence, Nature Cell Biology 18, 979–992;
Parry AJ et al., 2018, NOTCH-mediated non-cell autonomous regulation of chromatin structure during senescence, Nature Communications 9, 1840.