Abstract A70: Studying the signaling pathways of tumorigenic epithelial fallopian tube subpopulations during early tumorigenesis

Survival rates for high-grade serous ovarian carcinoma (HGSOC) patients have not substantially improved over the past decades, mainly because the disease is only detected at the metastatic stage. The findings of early premalignant lesions in the fallopian tube, but not in the ovary, suggested that HGSOCs may originate from the fallopian tube epithelium (FTE) and metastasize to the ovary. Studying the mechanisms of HGSOC genesis from the correct cell of origin is critical to the early detection of the disease. Our main goal is to determine how genetic and molecular alterations contribute to the early events of HGSOC genesis from FTE. Deletion of PTEN alone in FTE is sufficient to lead to tumor formation and peritoneal dissemination, suggesting that loss of PTEN may play a pivotal role in the early events of the tumorigenic cascade. Herein we show that loss of PTEN in the FTE upregulates markers of tumor-initiating cells (TIC) such as WNT4, LGR5, ALDH1, c-Kit, CD44, and Dll4. We also discovered that the TIC markers are confined in a specific population of cells with increased diameter that we call TICHigh as compared to a smaller population that we call TICLow. In fact, when these two populations are separated by flow cytometry-based sorting, the TICHigh retains all the TIC markers. In addition, using a limiting dilution assay, we found that the TICHigh subpopulation forms tumor at a faster rate in vivo and colonize more the ovary ex vivo. In addition, TICHigh forms bigger spheroids and are more resistant to chemotherapeutic agents, suggesting that more targeted therapy may be developed for these stem-like, tumorigenic subpopulations. We also show that loss of PAX2 is mediating the TICHigh phenotype and that activation of AKT is not sufficient to induce the TIC phenotype whereas p70S6K activation is required. These findings suggest that therapies to re-express PAX2 may prevent development of HGSOC. Together, these findings provide a novel model to study the mechanism of fallopian tube tumor initiation and invasion to the ovary mediated by loss of PTEN, which may help to define early events of human ovarian carcinogenesis. Citation Format: Angela Russo, Matthew Dean, Dan Lantvit, Joanna E. Burdette. Studying the signaling pathways of tumorigenic epithelial fallopian tube subpopulations during early tumorigenesis [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr A70.