Abstract DP-012: STUDYING THE SIGNALING PATHWAYS OF DISTINCT SUBPOPULATIONS OF CELLS GENERATED UPON PTEN DELETION FROM FTE AND IDENTIFICATION OF MARKERS OF EARLY TUMORIGENESIS

Abstract

Abstract SIGNIFICANCE: High Grade Serous Cancer (HGSOC) Requires Novel Biomarkers for early detection. Survival rates for 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 pre-malignant 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. Recent transgenic animal models of FTE-derived HGSOC have pointed out the critical role of loss of PTEN (phosphatase and tensin homolog) from FTE in generating HGSOC when in combination with p53 mutation and alteration of BRCA1/2, but not by itself. Our lab was the first to show that deletion of PTEN alone in FTE is sufficient to lead to tumor formation and peritoneal dissemination suggesting that the importance of PTEN in the early events of the tumorigenic cascade may have been underestimated. Loss of PTEN from FTE is sufficient to drive ovarian cancer, however, the key signaling driving tumorigenesis when PTEN expression is low remain poorly defined and yet pivotal to new treatment options given its common occurrence. Studying the progression of HGSOC genesis from FTE is essential to refining the strategy for targeted therapies and to discovering novel biomarkers for early detection of the disease. PURPOSE: to identify signaling pathways and drug response of different subpopulations of tumorigenic cells generated upon PTEN deletion. RESULTS: Loss of PTEN in the FTE upregulates markers of cancer stem cells (CSC) such as WNT4, LGR5, ALDH1, c-Kit, CD44, and Dll4. We also discovered that the CSC markers are confined in a specific subpopulation of cells with increased diameter that we call CSCHigh as compared to a smaller population that we call CSCLow. In fact, when these two populations are separated by flow cytometry based sorting, the CSCHigh retains all the CSC markers. In addition, using a limiting dilution assay, we found that the CSCHigh subpopulation forms tumor at a faster rate in vivo. In addition, CSCHigh 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 CSCHigh phenotype suggesting that therapies to re-express PAX2 may prevent development of HGSOC. CONCLUSIONS: 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, Austin A. Czarnecki, Matthew Dean, Dan Lantvit, Jian-Jun Wei Joanna E. Burdette. STUDYING THE SIGNALING PATHWAYS OF DISTINCT SUBPOPULATIONS OF CELLS GENERATED UPON PTEN DELETION FROM FTE AND IDENTIFICATION OF MARKERS OF EARLY TUMORIGENESIS [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr DP-012.