Abstract LB318: Exploring early precursor lesions of ovarian cancer: Insights from an in vitro model

Abstract Ovarian cancer ranks as the fifth leading cause of cancer-related deaths in women, surpassing other cancers of the female reproductive system. Recent epidemiological and molecular studies highlight the significance of high-grade serous carcinoma (HGSC), the most aggressive subtype of ovarian cancer, constituting nearly 96% of cases with mutations in p53. HGSC originates from fallopian tube secretory epithelial (FTSEC) cells through a progression of precursor lesions, ranging from p53 signatures to serous tubal intraepithelial carcinoma (STIC). The p53 signature involves a linear expansion of over 12 TP53 mutant FTSECs, morphologically normal and displaying no increase in proliferative activity. In this study, we established a model system for P53 signature by either overexpressing p53 mutations (R175H and R273H) or knocking down P53 expression in normal FTSECs maintained as 2D, 3D, or organoid cultures. We have characterized the cells using RNA seq, mass spectroscopy and functional assays. Functional assays revealed increased migration and proliferation, along with decreased apoptosis in response to the cytotoxic stimulus (cisplatin). Despite the inability of p53 signature cells to proliferate or migrate in vivo, our hypothesis posited that clonal expansion of progenitor cell with a p53 mutation maintains plasticity by preserving the stemness of one or more cells capable of responding to cues from the microenvironment. Our experiments revealed heterogeneity in the model system, reflecting the composition of p53 signature in vivo. We also observed that stem-like cells tend to organize into clusters. Notably, stem-like cluster cells bearing a p53 signature exhibit migratory behavior, whereas clusters lacking p53 do not demonstrate such mobility. Given that most high-grade serous carcinoma (HGSC) cases occur in postmenopausal women, we demonstrated induction of proliferation and migration of p53 mutant stem cells in response to stimuli from aging stromal cells (fibroblasts and autologous immune cells) and to changes in hormonal background in our model. Conclusion: This study illuminates a novel aspect of ovarian cancer development, underscoring the role of a distinct population of fallopian tube epithelial cells with stem-like properties within p53 signatures. Further investigations into the tumorigenicity of these cells hold promise for providing valuable insights into future therapeutic strategies. Citation Format: Yan E. Wang, Vera Levina, Deborah L. Galson, Anna E. Lokshin. Exploring early precursor lesions of ovarian cancer: Insights from an in vitro model abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (7Suppl): Abstract nr LB318.