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

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 previously unrecognized cancer-prone cell state
and point to pre-ciliation mechanisms as novel diagnostic and therapeutic
targets.