Role of CD10 negative stroma in the development of precursor lesion of endometriosis associated ovarian cancer

Abstract Introduction: Ovarian clear cell carcinoma (OCCC) is a rare, aggressive, chemo-resistant subtype of epithelial ovarian cancer, and is associated with a significantly worse five-year survival compared to other ovarian cancer types. This is in part due to its distinct cell of origin which is thought to arise within sites of endometriosis. Atypical endometriosis is considered a precursor lesion of endometriosis-associated ovarian cancers, including OCCC. However, the mechanism underlying the development of atypical endometriosis and subsequent malignant transformation is still unknown. We recently demonstrated the existence of a OCCC tumor-promoting mesenchymal stem cell (enMSCs), marked by the loss of CD10 expression, within the endometriotic microenvironment. Further, we demonstrated that CD10 negative enMSCs selectively enhance OCCC growth, but not high-grade serous ovarian cancer (HGSOC) growth which provides further evidence that the endometriotic microenvironment is uniquely supportive of OCCC tumorigenesis. Thus, we hypothesized that loss of stromal CD10 expression leads to the creation of the precursor microenvironment for OCCC. Methods: EnMSCs and endometriosis epithelial cells were isolated from endometriosis tissue. Tissues were collected from women who undergo surgery for benign endometriosis. Based on surface CD10 expression, enMSCs were divided into CD10 negative or positive populations. Endometriosis epithelium proliferation was assessed using in vitro assays. Long term organoid of CD10 negative enMSCs and endometriosis epithelium were implanted into NSG mice to assess tumor initiation capacity. Results: Our data showed that co-culture with CD10 negative enMSCs enhanced the proliferation of endometriosis epithelium. Further, CD10 negative enMSCs enhanced the sphere formation capacity (sphere number and sphere size) of endometriosis epithelial cells when compared to endometriosis epithelium co-cultured with CD10 positive enMSCs or cultured alone. Furthermore, long term growth of organoids containing CD10 negative enMSCs and endometriosis epithelium stimulated the development of cytologic atypia in the epithelial cells. Strikingly, these organoids, when injected into the fat pad of NSG mice, initiated localized tumors. In summary, our data highlighted the role of CD10 negative enMSCs in the development of cytologic atypia in endometriosis epithelium and inducing tumor formation in vivo. This work has the potential for significant clinical impact as identification of a stromal biomarker for OCCC development would have important implications in the clinical management of women with endometriosis, including determining the need for risk-reducing surgery. Further, this work has the potential to identify new targets to disrupt the unique microenvironment of OCCC, thus providing new therapeutic strategies for this deadly disease. Citation Format: Huda Issa Atiya, Lan Coffman. Role of CD10 negative stroma in the development of precursor lesion of endometriosis associated ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3045.