Ciliated Cells Drive Critical STING-Mediated Tumor Suppression in the Fallopian Tube Epithelium

Area of Science:

• Gynecologic oncology
• Cellular and molecular biology
• Cancer genomics

Background:

• Fallopian tube epithelium (FTE) DNA damage is a precursor to tubo-ovarian high-grade serous carcinoma (HGSC).
• Ciliated cells within the FTE are increasingly recognized for their role in maintaining epithelial integrity.

Purpose of the Study:

• To investigate the role of stimulator of interferon genes (STING) in FTE ciliated cells.
• To elucidate the mechanisms by which ciliated cells prevent DNA damage accumulation and HGSC initiation.

Main Methods:

• Analysis of human patient samples and established mouse models.
• Utilized organoid systems to model FTE responses to genotoxic stress.
• Investigated STING expression and function in ciliated cells.
• Assessed the role of p53 signaling in protective mechanisms.

Main Results:

• STING is highly expressed in FTE ciliated cells, acting as an immune-independent tumor suppressor.
• Ciliated cells employ dual protective mechanisms: STING-dependent apoptosis and TNFα-mediated clearance of damaged secretory cells.
• These mechanisms effectively limit DNA damage but are dependent on functional p53 signaling.
• Loss of STING-high ciliated cells is implicated in HGSC initiation, particularly in p53-deficient contexts.

Conclusions:

• Ciliated cells are active gatekeepers of genomic integrity in the FTE, not passive bystanders.
• Early loss of STING-expressing ciliated cells is a critical event in HGSC development.
• Understanding these mechanisms may inform novel prevention and treatment strategies for HGSC.