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 u...
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| Format: | Article |
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Nature Portfolio
2024-10-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-52984-1 |
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| author | Andrea Flesken-Nikitin Coulter Q. Ralston Dah-Jiun Fu Andrea J. De 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 Alexander Yu. Nikitin |
| author_facet | Andrea Flesken-Nikitin Coulter Q. Ralston Dah-Jiun Fu Andrea J. De 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 Alexander Yu. Nikitin |
| author_sort | Andrea Flesken-Nikitin |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-90512a4f897946e0b160380da2b3bd0c |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2024-10-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-90512a4f897946e0b160380da2b3bd0c2024-11-24T12:32:29ZengNature PortfolioNature Communications2041-17232024-10-0115111610.1038/s41467-024-52984-1Pre-ciliated tubal epithelial cells are prone to initiation of high-grade serous ovarian carcinomaAndrea Flesken-Nikitin0Coulter Q. Ralston1Dah-Jiun Fu2Andrea J. De Micheli3Daryl J. Phuong4Blaine A. Harlan5Christopher S. Ashe6Amanda P. Armstrong7David W. McKellar8Sangeeta Ghuwalewala9Lora H. Ellenson10John C. Schimenti11Benjamin D. Cosgrove12Alexander Yu. Nikitin13Department of Biomedical Sciences, Cornell UniversityDepartment of Biomedical Sciences, Cornell UniversityDepartment of Biomedical Sciences, Cornell UniversityDepartment of Oncology and Children’s Research Center, University Children’s Hospital ZürichDepartment of Biomedical Sciences, Cornell UniversityDepartment of Biomedical Sciences, Cornell UniversityDepartment of Biomedical Sciences, Cornell UniversityDepartment of Biomedical Sciences, Cornell UniversityMeinig School of Biomedical Engineering, Cornell UniversityDepartment of Molecular Biology and Genetics, Cornell UniversityMemorial Sloan Kettering Cancer CenterDepartment of Biomedical Sciences, Cornell UniversityMeinig School of Biomedical Engineering, Cornell UniversityDepartment of Biomedical Sciences, Cornell UniversityAbstract 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.https://doi.org/10.1038/s41467-024-52984-1 |
| spellingShingle | Andrea Flesken-Nikitin Coulter Q. Ralston Dah-Jiun Fu Andrea J. De 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 Alexander Yu. Nikitin Pre-ciliated tubal epithelial cells are prone to initiation of high-grade serous ovarian carcinoma Nature Communications |
| title | Pre-ciliated tubal epithelial cells are prone to initiation of high-grade serous ovarian carcinoma |
| title_full | Pre-ciliated tubal epithelial cells are prone to initiation of high-grade serous ovarian carcinoma |
| title_fullStr | Pre-ciliated tubal epithelial cells are prone to initiation of high-grade serous ovarian carcinoma |
| title_full_unstemmed | Pre-ciliated tubal epithelial cells are prone to initiation of high-grade serous ovarian carcinoma |
| title_short | Pre-ciliated tubal epithelial cells are prone to initiation of high-grade serous ovarian carcinoma |
| title_sort | pre ciliated tubal epithelial cells are prone to initiation of high grade serous ovarian carcinoma |
| url | https://doi.org/10.1038/s41467-024-52984-1 |
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