Pre-ciliated tubal epithelial cells are prone to initiation of high-grade serous ovarian carcinoma Journal Article
| Authors: | Flesken-Nikitin, A.; Ralston, C. Q.; Fu, D. J.; De Micheli, A. J.; Phuong, D. J.; Harlan, B. A.; Ashe, C. S.; Armstrong, A. P.; McKellar, D. W.; Ghuwalewala, S.; Ellenson, L. H.; Schimenti, J. C.; Cosgrove, B. D.; Nikitin, A. Y. |
| Article Title: | Pre-ciliated tubal epithelial cells are prone to initiation of high-grade serous ovarian carcinoma |
| 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. © The Author(s) 2024. |
| Keywords: | controlled study; genetics; nonhuman; ovarian neoplasms; mouse; animal; metabolism; animals; mice; apoptosis; cell differentiation; pathology; inhibitor; protein p53; stem cell; cell transformation, neoplastic; ovary; ovary tumor; carcinoma in situ; ovary carcinoma; epithelium cell; epithelial cells; tumor suppressor protein p53; cystadenocarcinoma, serous; malignant transformation; uterus cancer; retinoblastoma protein; cilia; cystadenocarcinoma; fallopian tubes; inhibition; fallopian tube; cell component; cancer; humans; human; female; article; organoid; cilium; neoplastic cell transformation; ciliated epithelium cell; trp53 protein, mouse |
| Journal Title: | Nature Communications |
| Volume: | 15 |
| ISSN: | 2041-1723 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2024-10-05 |
| Start Page: | 8641 |
| Language: | English |
| DOI: | 10.1038/s41467-024-52984-1 |
| PUBMED: | 39366996 |
| PROVIDER: | scopus |
| PMCID: | PMC11452611 |
| DOI/URL: | |
| Notes: | Erratum issued, DOI: 10.1038/s41467-024-54465-x -- Source: Scopus |
