Molecular subtyping of endometrial carcinoma cell lines uncovers subtype-specific targetable vulnerabilities

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)...

Full description

Saved in:
Bibliographic Details
Main Authors: 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
Format: Article
Language:English
Published: Nature Portfolio 2025-07-01
Series:npj Precision Oncology
Online Access:https://doi.org/10.1038/s41698-025-01053-x
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:2397-768X

Similar Items