Molecular subtyping of endometrial carcinoma cell lines uncovers subtype-specific targetable vulnerabilities
Abstract Endometrial carcinoma (EC), the most common gynecologic cancer type in developed countries, encompasses four molecular subtypes (POLEmut, MMRd, p53abn, and NSMP) that have prognostic values and guide treatment decisions. Additionally, dual loss of ARID1A and ARID1B (referred to as ARID1A/B)...
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Nature Portfolio
2025-07-01
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| Series: | npj Precision Oncology |
| Online Access: | https://doi.org/10.1038/s41698-025-01053-x |
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| author | Eunice S. Li Rebecca Ho Ran Tao Yannes Wai Yan Choi Chae Young Shin Shary Y. Chen Bengul Gokbayrak Janine Senz Betty Yao Liam Johnston Spencer D. Martin Eric Yang Mark S. Carey Bryan T. Hennessy David G. Huntsman Ramon I. Klein Geltink Lynn Hoang Yemin Wang |
| author_facet | Eunice S. Li Rebecca Ho Ran Tao Yannes Wai Yan Choi Chae Young Shin Shary Y. Chen Bengul Gokbayrak Janine Senz Betty Yao Liam Johnston Spencer D. Martin Eric Yang Mark S. Carey Bryan T. Hennessy David G. Huntsman Ramon I. Klein Geltink Lynn Hoang Yemin Wang |
| author_sort | Eunice S. Li |
| collection | DOAJ |
| description | Abstract Endometrial carcinoma (EC), the most common gynecologic cancer type in developed countries, encompasses four molecular subtypes (POLEmut, MMRd, p53abn, and NSMP) that have prognostic values and guide treatment decisions. Additionally, dual loss of ARID1A and ARID1B (referred to as ARID1A/B) characterizes a significant portion of dedifferentiated/undifferentiated EC (DD/UDEC), a rare but highly aggressive subtype of EC. To advance the translational research for ECs, we analyzed the genomic features of a panel of 39 EC cell lines, leading to the identification of cell lines representing each of these EC molecular subtype. Histologic and immunohistochemical analyses of xenografted tumors from these cell lines confirmed their resemblance of cognate primary EC molecular subtypes. Further investigation of the publicly available genome-wide CRISPR screen data for EC cell lines identified multiple specific genetic dependencies in MMRd, p53abn, and ARID1A/B-dual deficient EC cell lines. Particularly, ARID1A/B-dual deficient DD/UDEC cells selectively rely on mitochondrial oxidative phosphorylation in vitro and in vivo. Therefore, through molecular subtyping of EC cell lines and subsequent characterization of molecular subtype-specific genetic dependencies, our study provides a framework that guides the utility of the EC cell line models for accelerating translational research in EC. |
| format | Article |
| id | doaj-art-bff4d2c15a7a4ca7b3f5d53fa4f989ac |
| institution | Kabale University |
| issn | 2397-768X |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | npj Precision Oncology |
| spelling | doaj-art-bff4d2c15a7a4ca7b3f5d53fa4f989ac2025-08-20T04:01:47ZengNature Portfolionpj Precision Oncology2397-768X2025-07-019111210.1038/s41698-025-01053-xMolecular subtyping of endometrial carcinoma cell lines uncovers subtype-specific targetable vulnerabilitiesEunice S. Li0Rebecca Ho1Ran Tao2Yannes Wai Yan Choi3Chae Young Shin4Shary Y. Chen5Bengul Gokbayrak6Janine Senz7Betty Yao8Liam Johnston9Spencer D. Martin10Eric Yang11Mark S. Carey12Bryan T. Hennessy13David G. Huntsman14Ramon I. Klein Geltink15Lynn Hoang16Yemin Wang17Department of Pathology and Laboratory Medicine, University of British ColumbiaDepartment of Pathology and Laboratory Medicine, University of British ColumbiaDepartment of Pathology and Laboratory Medicine, University of British ColumbiaDepartment of Pathology and Laboratory Medicine, University of British ColumbiaDepartment of Pathology and Laboratory Medicine, University of British ColumbiaDepartment of Pathology and Laboratory Medicine, University of British ColumbiaDepartment of Pathology and Laboratory Medicine, University of British ColumbiaDepartment of Pathology and Laboratory Medicine, University of British ColumbiaDepartment of Pathology and Laboratory Medicine, University of British ColumbiaDepartment of Pathology and Laboratory Medicine, University of British ColumbiaDepartment of Pathology and Laboratory Medicine, University of British ColumbiaDepartment of Pathology and Laboratory Medicine, University of British ColumbiaDepartment of Obstetrics and Gynecology, University of British ColumbiaRoyal College of Surgeons in IrelandDepartment of Pathology and Laboratory Medicine, University of British ColumbiaDepartment of Pathology and Laboratory Medicine, University of British ColumbiaDepartment of Pathology and Laboratory Medicine, University of British ColumbiaDepartment of Pathology and Laboratory Medicine, University of British ColumbiaAbstract Endometrial carcinoma (EC), the most common gynecologic cancer type in developed countries, encompasses four molecular subtypes (POLEmut, MMRd, p53abn, and NSMP) that have prognostic values and guide treatment decisions. Additionally, dual loss of ARID1A and ARID1B (referred to as ARID1A/B) characterizes a significant portion of dedifferentiated/undifferentiated EC (DD/UDEC), a rare but highly aggressive subtype of EC. To advance the translational research for ECs, we analyzed the genomic features of a panel of 39 EC cell lines, leading to the identification of cell lines representing each of these EC molecular subtype. Histologic and immunohistochemical analyses of xenografted tumors from these cell lines confirmed their resemblance of cognate primary EC molecular subtypes. Further investigation of the publicly available genome-wide CRISPR screen data for EC cell lines identified multiple specific genetic dependencies in MMRd, p53abn, and ARID1A/B-dual deficient EC cell lines. Particularly, ARID1A/B-dual deficient DD/UDEC cells selectively rely on mitochondrial oxidative phosphorylation in vitro and in vivo. Therefore, through molecular subtyping of EC cell lines and subsequent characterization of molecular subtype-specific genetic dependencies, our study provides a framework that guides the utility of the EC cell line models for accelerating translational research in EC.https://doi.org/10.1038/s41698-025-01053-x |
| spellingShingle | Eunice S. Li Rebecca Ho Ran Tao Yannes Wai Yan Choi Chae Young Shin Shary Y. Chen Bengul Gokbayrak Janine Senz Betty Yao Liam Johnston Spencer D. Martin Eric Yang Mark S. Carey Bryan T. Hennessy David G. Huntsman Ramon I. Klein Geltink Lynn Hoang Yemin Wang Molecular subtyping of endometrial carcinoma cell lines uncovers subtype-specific targetable vulnerabilities npj Precision Oncology |
| title | Molecular subtyping of endometrial carcinoma cell lines uncovers subtype-specific targetable vulnerabilities |
| title_full | Molecular subtyping of endometrial carcinoma cell lines uncovers subtype-specific targetable vulnerabilities |
| title_fullStr | Molecular subtyping of endometrial carcinoma cell lines uncovers subtype-specific targetable vulnerabilities |
| title_full_unstemmed | Molecular subtyping of endometrial carcinoma cell lines uncovers subtype-specific targetable vulnerabilities |
| title_short | Molecular subtyping of endometrial carcinoma cell lines uncovers subtype-specific targetable vulnerabilities |
| title_sort | molecular subtyping of endometrial carcinoma cell lines uncovers subtype specific targetable vulnerabilities |
| url | https://doi.org/10.1038/s41698-025-01053-x |
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