A complex secretory program orchestrated by the inflammasome controls paracrine senescence

Area of Science:

• Cellular senescence
• Tumor immunology
• Molecular biology

Background:

• Oncogene-induced senescence (OIS) is a critical tumor suppressive mechanism.
• Senescent cells release the senescence-associated secretory phenotype (SASP), a complex inflammatory mix.
• The SASP has dual roles: reinforcing senescence and immune activation, yet also promoting tumorigenesis.

Purpose of the Study:

• To investigate the capacity of the SASP to induce paracrine senescence in normal cells.
• To identify specific SASP components responsible for mediating paracrine senescence.
• To elucidate the signaling pathways controlling SASP-induced paracrine senescence.

Main Methods:

• Quantitative proteomics to identify SASP components.
• Small-molecule screens to find mediators of paracrine senescence.
• In vitro cell culture and in vivo mouse models of OIS.

Main Results:

• The SASP was demonstrated to induce paracrine senescence in normal cells.
• Key SASP mediators identified include TGF-β ligands, VEGF, CCL2, and CCL20.
• TGF-β ligands were shown to regulate p15(INK4b) and p21(CIP1) in paracrine senescence.
• Inflammasome-mediated IL-1 signaling controls SASP expression, with IL-1α activating SASP and senescence.

Conclusions:

• The SASP can induce paracrine senescence, impacting tumor suppression.
• IL-1 signaling is a key regulator of SASP-driven paracrine senescence.
• These findings offer new perspectives on the role of SASP in vivo and its implications for cancer.