Cell State of Origin Impacts Development of Distinct Endometriosis-Related Ovarian Carcinoma Histotypes

Authors

Ian Beddows
Huihui Fan
Karolin Heinze
Benjamin K Johnson
Anna Leonova
Janine Senz
Svetlana Djirackor
Kathleen R Cho
Celeste Leigh Pearce
David G Huntsman
Michael S Anglesio
Hui Shen

Publication Date

1-2-2024

Journal

Cancer Research

Abstract

Clear cell ovarian carcinoma (CCOC) and endometrioid ovarian carcinoma (ENOC) are ovarian carcinoma histotypes, which are both thought to arise from ectopic endometrial (or endometrial-like) cells through an endometriosis intermediate. How the same cell type of origin gives rise to two morphologically and biologically different histotypes has been perplexing, particularly given that recurrent genetic mutations are common to both and present in nonmalignant precursors. We used RNA transcription analysis to show that the expression profiles of CCOC and ENOC resemble those of normal endometrium at secretory and proliferative phases of the menstrual cycle, respectively. DNA methylation at the promoter of the estrogen receptor (ER) gene (ESR1) was enriched in CCOC, which could potentially lock the cells in the secretory state. Compared with normal secretory-type endometrium, CCOC was further defined by increased expression of cysteine and glutathione synthesis pathway genes and downregulation of the iron antiporter, suggesting iron addiction and highlighting ferroptosis as a potential therapeutic target. Overall, these findings suggest that while CCOC and ENOC arise from the same cell type, these histotypes likely originate from different cell states. This "cell state of origin" model may help to explain the presence of histologic and molecular cancer subtypes arising in other organs.

Keywords

Female, Humans, Endometriosis, Ovarian Neoplasms, Carcinoma, Endometrioid, Carcinoma, Ovarian Epithelial, Adenocarcinoma, Clear Cell, Iron

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Supplementary Materials

PMID: 37874327