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

Abstract

AbstractThe 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 markerSlc1a3can differentiate into both secretory (Ovgp1+) and ciliated (Fam183b+) cells. Inactivation ofTrp53andRb1, whose pathways are commonly altered in HGSC, leads to elimination of targetedSlc1a3+ 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 previously unrecognized cancer-prone cell state and point to pre-ciliation mechanisms as novel diagnostic and therapeutic targets.