Intracellular signaling modules linking DNA damage to secretome changes in senescent melanoma cells

Area of Science:

• Oncology
• Cellular Biology
• Cancer Research

Background:

• Cellular senescence acts as a tumor suppressor, but secreted proteins from senescent cells can influence cancer progression.
• Melanoma development involves genetic alterations that induce cellular senescence, impacting tumorigenesis and therapy response.
• Mechanistic understanding of melanoma cell senescence and its clinical implications remains limited.

Purpose of the Study:

• To establish and characterize a melanoma cell senescence model.
• To investigate the signaling pathways and secreted proteins involved in melanoma cell senescence.
• To identify potential therapeutic targets and biomarkers for melanoma.

Main Methods:

• Pharmacologically induced DNA damage to trigger senescence in melanoma cells.
• Targeted proteome profiling to analyze secreted proteins.
• CRISPR-mediated genetic ablation to dissect signaling pathways (ATM, STING, p38α, IKKβ).

Main Results:

• Senescent melanoma cells exhibited cell cycle arrest, altered morphology, and significant secretome changes.
• Senescent cells secreted proteins that modulate the tumor immune microenvironment.
• ATM kinase and STING signaling pathways were differentially involved in senescence induction and secretome changes.
• Genetic ablation of p38α and IKKβ disrupted the link between DNA damage and secretion without restoring proliferation.
• STING signaling loss prevented type I interferon induction but did not affect other senescence processes.

Conclusions:

• Senescent melanoma cells secrete proteins with potential as biomarkers and therapeutic targets.
• ATM and STING signaling pathways play distinct roles in melanoma cell senescence.
• Understanding these pathways can inform melanoma treatment strategies.