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

Flesken-Nikitin, A.; Ralston, C. Q.; Fu, D.-J.; De Micheli, A. J.; Phuong, D. J.; Harlan, B. A.; Armstrong, A. P.; McKellar, D.; Ghuwalewala, S.; Schimenti, J. C.; Cosgrove, B. D.; Nikitin, A. Y.

doi:10.1101/2023.12.12.571315

bioRxiv · 10.1101/2023.12.12.571315

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

Flesken-Nikitin, A.·Ralston, C. Q.·Fu, D.-J.·De Micheli, A. J.·Phuong, D. J.·Harlan, B. A.·Armstrong, A. P.·McKellar, D.·Ghuwalewala, S.·Schimenti, J. C.·Cosgrove, B. D.·Nikitin, A. Y.

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

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Flesken-Nikitin, A., Ralston, C. Q., Fu, D.-J., De Micheli, A. J., Phuong, D. J., Harlan, B. A., Armstrong, A. P., McKellar, D., Ghuwalewala, S., Schimenti, J. C., Cosgrove, B. D., Nikitin, A. Y.. 2023-12-13. Pre-ciliated tubal epithelial cells are prone to initiation of high-grade serous ovarian carcinoma. https://doi.org/10.1101/2023.12.12.571315

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