Aged and BRCA-Mutated Stromal Cells Drive Epithelial Cell Transformation

Area of Science:

• Oncology
• Cell Biology
• Stem Cell Biology

Background:

• High-grade serous ovarian cancer (HGSOC) initiation mechanisms remain poorly understood, hindering prevention and early detection efforts.
• Existing models suggest transformation of fallopian tube epithelial (FTE) cells into precursor lesions (STIC) leading to HGSOC.

Purpose of the Study:

• To investigate the role of mesenchymal stem cell niches in HGSOC initiation prior to STIC lesion formation.
• To identify novel cellular players involved in the early stages of ovarian cancer development.

Main Methods:

• Characterization of epigenetically altered mesenchymal stromal/stem cells (hrMSCs) in the fallopian tube microenvironment.
• Assessment of hrMSC interactions with FTE cells, including DNA damage and survival effects.
• In vivo studies to evaluate the role of hrMSCs in inducing malignant transformation and metastasis.

Main Results:

• Identified a novel cell population, hrMSCs, present before STIC lesions and enriched in STIC stroma.
• Demonstrated that hrMSCs promote DNA damage and survival in FTE cells, leading to malignant transformation and metastasis in vivo.
• Found hrMSCs are significantly enriched in BRCA1/2 mutation carriers and increase with age.

Conclusions:

• hrMSCs play a critical role in inciting HGSOC initiation through stromal-mediated epithelial transformation.
• These findings have significant implications for developing new strategies for ovarian cancer detection and prevention.
• The identification of hrMSCs provides a new perspective on cancer initiation, potentially applicable across various cancer types.