Abstract A014: Role of stromal CD10 expression in progression of endometrial and endometriosis-associated cancers

Abstract

Abstract Endometriosis-associated carcinomas (EACs) and endometrial malignancies have many commonalities yet their pathophysiology, particularly those with high-risk histology such as clear cell, is understudied. EACs are histologically and clinically distinct from other gynecological cancers due to their unique origin within endometriosis. The endometriotic microenvironment is uniquely hypoxic with high levels of iron due to recurrent menstrual cycling, and this iron-rich microenvironment has been linked to promoting carcinogenesis through iron-induced oxidative stress. However, the mechanism by which the endometriotic microenvironment contributes to EAC tumorigenesis and how this compares with endometrial cancer is unknown. Most of our current knowledge of EACs is built on either epidemiologic analyses or correlative studies. Additionally, most studies of the endometriotic microenvironment primarily focus on the epithelial component while the role of the stroma has been largely unexplored. Mesenchymal stem cells (MSC) are a critical component of the stromal microenvironment. Recently, we identified a key role of endometriosis derived MSCs (enMSCs) in altering ovarian clear cell carcinoma iron regulation. Interestingly, enMSCs resemble the primary endometrium derived MSCs, which suggested their role in endometrial cancer. This stromal subset is characterized by the loss of surface CD10 expression. It is known that cancer cells, particularly clear cell carcinoma (CCC), have a unique requirement for high levels of iron. We hypothesize that CD10 negative enMSCs promote growth of EAC and endometrial cancer through iron regulation. MSCs were isolated from primary human benign endometriosis, benign endometrium, or endometrial cancer. Flow cytometry was used to measure surface CD10 expression. We investigated the role of CD10 negative enMSCs on CCC iron regulation. Our results showed that CD10 negative enMSCs promote CCC growth by exporting iron through the upregulation of Hephaestin (HEPH) and Ferroportin (FPO) which then led to increase labile iron pool (LIP) in CCC cells. However, increasing the LIP does not occur with iron supplementation alone, this indicates the critical role of CD10 negative enMSCs in regulating iron handling in CCC cells. Additionally, our data showed that CD10 negative enMSCs alter the balance of Ferritin L and Ferritin H- the main iron storage proteins- in CCC cells. Mechanistically, our preliminary data showed that CD10 negative enMSCs directly donate Ferritin L into CCC cells. Further, CD10 negative enMSCs enhance Ferritin H degradation through the upregulation of ferritinophagy in CCC cells. In conclusion, our results indicate there is a sub-population of enMSCs, marked by the loss of CD10 expression, that enhances EAC and endometrial cancer cell growth through iron regulation. This highlights the existence of a tumor-promoting stromal cell within both the endometrium and endometriosis which can be capitalized on as an “Achilles' heel” to uncover novel treatment targets for EAC and endometrial cancer. Citation Format: Huda I. Atiya, Lan G. Coffman. Role of stromal CD10 expression in progression of endometrial and endometriosis-associated cancers [abstract]. In: Proceedings of the AACR Special Conference on Endometrial Cancer: Transforming Care through Science; 2023 Nov 16-18; Boston, Massachusetts. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(5_Suppl):Abstract nr A014.