Oncogenic Events Dictate the Types and Locations of Gynecological Malignancies Originating from Krt8(+) Mesothelial and Müllerian-Derived Epithelial Cells

SIMPLE SUMMARY: Ovarian and uterine cancers are the most common gynecological malignancies in women. The early detection, prevention, and treatment of these gynecological cancers can benefit from a better understanding of how tumor-initiating cells in them are formed from their corresponding target cell populations in the female reproductive system. To study this, we utilized a genetic approach in mice to introduce driver mutations commonly found in these cancers to Keratin 8 positive (K8(+)) mesothelial and epithelial cells in the ovary, fallopian tube, and uterus. We found that p53-loss appears to preferentially affect K8(+) epithelial cells, leading to the development of uterine and ovarian malignancies, whereas PTEN-loss may preferentially affect mesothelial cells, leading to the development of ovarian endometrioid malignancies or adenoma on the fallopian tube surface. Collectively, our data suggest that oncogenic driver mutations may dominantly determine the locations and types of gynecological malignancies developed from K8(+) mesothelial and epithelial cells in the female reproductive system. ABSTRACT: Ovarian and uterine cancers are the most prevalent types of gynecological malignancies originating from mesothelial and/or Müllerian-derived epithelial cells. Recent genomic studies have identified common mutations in them that affect signaling pathways such as p53, PTEN/PI3K, RAS, and WNT pathways. However, how these mutations and their corresponding deregulated pathways affect gynecological cancer development from their cells-of-origin remains largely elusive. To address this, we performed the intrabursal injection of Cre-expressing adenovirus under the control of Krt8 promoter (Ad-K8-Cre) to mice carrying combinations of various conditional alleles for cancer genes. We found that Ad-K8-Cre specifically targeted mesothelial cells, including ovarian surface epithelial (OSE) cells (mainly the LGR5(+) subset of OSE cells) and mesothelial cells lining the fallopian tube (FT) serosa; the injected Ad-K8-Cre also targeted Müllerian-derived epithelial cells, including FT epithelial cells and uterine endometrial epithelial cells. The loss of p53 may preferentially affect Müllerian-derived epithelial cells, leading to the development of uterine and ovarian malignancies, whereas PTEN-loss may preferentially affect mesothelial cells, leading to the development of ovarian endometrioid malignancies (upon KRAS-activation or APC-loss) or adenoma on the FT surface (upon DICER-loss). Overall, our data suggest that different Krt8(+) mesothelial and epithelial cell types in the female reproductive system may have different sensitivities toward oncogenic mutations and, as a result, oncogenic events may dominantly determine the locations and types of the gynecological malignancies developed from them.