NOTCH1 mediates a switch between two distinct secretomes during senescence

Abstract

Senescence, a persistent form of cell cycle arrest, is often associated with a diverse secretome, which provides complex functionality for senescent cells within the tissue microenvironment. We show that oncogene-induced senescence (OIS) is accompanied by a dynamic fluctuation of NOTCH1 activity, which drives a TGF-β-rich secretome, whilst suppressing the senescence-associated pro-inflammatory secretome through inhibition of C/EBPβ. NOTCH1 and NOTCH1-driven TGF-β contribute to ‘lateral induction of senescence’ through a juxtacrine NOTCH-JAG1 pathway. In addition, NOTCH1 inhibition during senescence facilitates upregulation of pro-inflammatory cytokines, promoting lymphocyte recruitment and senescence surveillance in vivo. Because enforced activation of NOTCH1 signalling confers a near mutually exclusive secretory profile compared to typical senescence, our data collectively indicate that the dynamic alteration of NOTCH1 activity during senescence dictates a functional balance between these two distinct secretomes: one representing TGF-β and the other pro-inflammatory cytokines, highlighting that NOTCH1 is a temporospatial controller of secretome composition.

Integrin Beta 3 Regulates Cellular Senescence by Activating the TGF-β Pathway

“…Though the mRNA levels of ITGB3 at early timepoints of the induction of senescence were downregulated, we did observe a consistent upregulation of ITGB3 during the establishment of senescence (Figure S3E). This pattern highly resembles the recently described temporal changes induced by NOTCH1 during OIS (Hoare et al., 2016). …”

The nuclear receptor RXRA controls cellular senescence by regulating calcium signaling

“…A significant induction of the expression of several other genes encoding SASP components was observed (BMP2, COL3A1, IGFBP5, MMP3, PDGFA, VEGFA; Supporting Information Figure S6c). Interestingly, PDGFA and COL3A1 were recently described as part of the distinct SASP driven by NOTCH1 (Hoare et al, 2016). Furthermore, RXRA knockdown decreased cell proliferation as we observed a drop in the expression of the cell proliferation marker Ki‐67 (Figure 5e and Supporting Information Figure S7) and a decrease in the number of cells (Figure 5f).…”

Telomere dysfunction promotes transdifferentiation of human fibroblasts into myofibroblasts

“…In these cells, the SASP develops dynamically and changes its composition in a temporal manner. Within a few hours after entering senescence, the secretome of human somatic fibroblasts is enriched in growth factors and includes transforming growth factor beta‐1 (TGF‐β1) (Hoare et al, 2016; Hubackova, Krejcikova, Bartek, & Hodny, 2012), a cytokine involved in wound healing where it promotes transdifferentiation of fibroblasts into myofibroblasts. After approximately four to six days in senescence, the TGF‐β1‐rich secretome changes as cells begin to secrete pro‐inflammatory cytokines that include interleukin 6 (IL‐6) and 8 (IL‐8) (Hoare et al, 2016).…”

“…Within a few hours after entering senescence, the secretome of human somatic fibroblasts is enriched in growth factors and includes transforming growth factor beta‐1 (TGF‐β1) (Hoare et al, 2016; Hubackova, Krejcikova, Bartek, & Hodny, 2012), a cytokine involved in wound healing where it promotes transdifferentiation of fibroblasts into myofibroblasts. After approximately four to six days in senescence, the TGF‐β1‐rich secretome changes as cells begin to secrete pro‐inflammatory cytokines that include interleukin 6 (IL‐6) and 8 (IL‐8) (Hoare et al, 2016). While it is still unclear why the SASP develops in phases, it has been suggested that the temporal evolution of the SASP may be important for orchestrating the distinct stages of tissue repair (Hoare & Narita, 2016; Schmitt, 2016).…”