NOTCH1 mediates a switch between two distinct secretomes during senescence

Area of Science:

• Cell Biology
• Molecular Biology
• Immunology

Background:

• Cellular senescence is a state of irreversible cell-cycle arrest.
• Senescent cells secrete a variety of factors (the secretome) that impact the tissue microenvironment.
• The composition of the senescence-associated secretome is complex and not fully understood.

Purpose of the Study:

• To investigate the role of NOTCH1 signaling in regulating the secretome during oncogene-induced senescence.
• To elucidate the mechanisms by which NOTCH1 influences distinct secretome profiles.
• To understand how NOTCH1 activity impacts senescence surveillance in vivo.

Main Methods:

• Induction of senescence using oncogenes.
• Analysis of NOTCH1 activity fluctuations during senescence.
• Assessment of secretome composition, including TGF-β and pro-inflammatory cytokines.
• Investigation of the NOTCH-JAG1 pathway.
• In vivo studies of senescence surveillance.

Main Results:

• Oncogene-induced senescence involves dynamic NOTCH1 activity.
• NOTCH1 drives a TGF-β-rich secretome and suppresses pro-inflammatory cytokines via C/EBPβ inhibition.
• NOTCH1-JAG1 signaling mediates lateral induction of senescence.
• NOTCH1 inhibition during senescence upregulates pro-inflammatory cytokines, enhancing lymphocyte recruitment and surveillance.
• Enforced NOTCH1 activation leads to a distinct secretory profile compared to typical senescence.

Conclusions:

• Dynamic NOTCH1 activity is a key regulator of secretome composition during senescence.
• NOTCH1 orchestrates a balance between TGF-β-rich and pro-inflammatory secretomes.
• NOTCH1 acts as a temporospatial controller of senescent cell function and tissue response.