Abstract IA007: Soil forming the seed: stromal drivers of ovarian cancer initiation

Abstract The underlying mechanism driving high-grade serous ovarian cancer (HGSOC) initiation are undefined. This lack of clarity raises significant barriers to the development of prevention or early detection strategies for this deadly disease. Most HGSOC arise in the distal fimbreated end from damages in the fallopian tube epithelium (FTE). These FTE cells undergo a transformation process to develop into serous tubal intraepithelial carcinoma (STIC) precursors and then to full blown cancer. We demonstrate that epigenetically altered mesenchymal stem cells (termed high risk MSC-hrMSCs) are present prior to the formation of ovarian cancer or their precursor lesions. These hrMSCs mediate DNA damage but also promote the survival of FTE cells setting the stage for cancer initiation. Indeed, we find hrMSCs induce full malignant transformation of otherwise healthy, primary FTE resulting in metastatic cancer in vivo. Further supporting a role for hrMSCs in cancer initiation in humans, we demonstrate that hrMSCs are enriched in women at highest risk for HGSOC including those with BRCA1/2 mutation carriers and older women. Collectively, these findings indicate that hrMSCs play a critical role in ovarian cancer initiation and have implications for ovarian cancer detection and prevention. Citation Format: Lan G. Coffman. Soil forming the seed: stromal drivers of ovarian cancer initiation [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 IA007.