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

Andrea Flesken-Nikitin, Coulter Q. Ralston, Dah-Jiun Fu, Andrea J. Micheli, Daryl J. Phuong, Blaine A. Harlan, Christopher S. Ashe, Amanda P. Armstrong, David W. McKellar, Sangeeta Ghuwalewala, Lora H. Ellenson, John C. Schimenti, Benjamin D. Cosgrove and Alexander Yu. Nikitin ()
Additional contact information
Andrea Flesken-Nikitin: Cornell University
Coulter Q. Ralston: Cornell University
Dah-Jiun Fu: Cornell University
Andrea J. Micheli: University Children’s Hospital Zürich
Daryl J. Phuong: Cornell University
Blaine A. Harlan: Cornell University
Christopher S. Ashe: Cornell University
Amanda P. Armstrong: Cornell University
David W. McKellar: Cornell University
Sangeeta Ghuwalewala: Cornell University
Lora H. Ellenson: Memorial Sloan Kettering Cancer Center
John C. Schimenti: Cornell University
Benjamin D. Cosgrove: Cornell University
Alexander Yu. Nikitin: Cornell University

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-52984-1

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