Abstract IA010: Understanding the cellular origins of ovarian cancer histotypes

Abstract Ovarian cancer is not a single disease but a collection of histotypes with distinct cellular origins and developmental pathways. Clear-cell and endometrioid ovarian carcinomas (CCOC and ENOC) are two histotypes that share an origin—ectopic endometrial epithelial cells associated with endometriosis. How the same cell type gives rise to morphologically and biologically different cancers remains unclear, particularly since both harbor recurrent mutations also present in non-malignant precursors. Our transcriptome analysis revealed that CCOC and ENOC recapitulate the expression profiles of normal endometrium in the secretory and proliferative phases of the menstrual cycle, respectively. In CCOC, DNA methylation at the estrogen receptor (ESR1) promoter may lock cells into a secretory-like state. These findings suggest that although CCOC and ENOC originate from the same cell type, they likely arise from distinct cell states at transformation. Several features previously considered CCOC-specific—such as HNF1B expression—are present in normal secretory endometrium. Compared with its normal counterpart, CCOC further upregulates cysteine and glutathione synthesis genes while downregulating the iron antiporter, consistent with iron dependency and highlighting ferroptosis as a potential therapeutic vulnerability. Recognizing the importance of baseline variation in cells of origin, we also examined the human fallopian tube, the primary site of most high-grade serous carcinomas. Using bulk assays to profile over 100 fallopian tubes spanning a wide range of age, menstrual cycle phase, surgical indication, and germline BRCA status, we identified five groups distinguished by their cell type and state compositions. In parallel, we developed a highly sensitive single-cell total RNA-seq method, enabling high-resolution mapping of these populations and discovery of a new candidate progenitor cell type. This integrative approach provides a framework for understanding the earliest steps of tumorigenesis across ovarian cancer histotypes. Citation Format: Hui Shen. Understanding the cellular origins of ovarian cancer histotypes [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Ovarian Cancer Research; 2025 Sep 19-21; Denver, CO. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl):Abstract nr IA010.