Pre-ciliated tubal epithelial cells are prone to initiation of high-grade serous ovarian carcinoma

Nat Commun. 2024 Oct 5;15(1):8641. doi: 10.1038/s41467-024-52984-1.

Abstract

The distal region of the uterine (Fallopian) tube is commonly associated with high-grade serous carcinoma (HGSC), the predominant and most aggressive form of ovarian or extra-uterine cancer. Specific cell states and lineage dynamics of the adult tubal epithelium (TE) remain insufficiently understood, hindering efforts to determine the cell of origin for HGSC. Here, we report a comprehensive census of cell types and states of the mouse uterine tube. We show that distal TE cells expressing the stem/progenitor cell marker Slc1a3 can differentiate into both secretory (Ovgp1+) and ciliated (Fam183b+) cells. Inactivation of Trp53 and Rb1, whose pathways are commonly altered in HGSC, leads to elimination of targeted Slc1a3+ cells by apoptosis, thereby preventing their malignant transformation. In contrast, pre-ciliated cells (Krt5+, Prom1+, Trp73+) remain cancer-prone and give rise to serous tubal intraepithelial carcinomas and overt HGSC. These findings identify transitional pre-ciliated cells as a cancer-prone cell state and point to pre-ciliation mechanisms as diagnostic and therapeutic targets.

MeSH terms

  • Animals
  • Cell Transformation, Neoplastic / pathology
  • Cilia* / metabolism
  • Cilia* / pathology
  • Cystadenocarcinoma, Serous* / metabolism
  • Cystadenocarcinoma, Serous* / pathology
  • Epithelial Cells* / metabolism
  • Epithelial Cells* / pathology
  • Fallopian Tubes* / pathology
  • Female
  • Humans
  • Mice
  • Ovarian Neoplasms* / metabolism
  • Ovarian Neoplasms* / pathology
  • Retinoblastoma Protein / genetics
  • Retinoblastoma Protein / metabolism
  • Tumor Suppressor Protein p53* / genetics
  • Tumor Suppressor Protein p53* / metabolism

Substances

  • Tumor Suppressor Protein p53
  • Trp53 protein, mouse
  • Retinoblastoma Protein