Regulation of Fallopian Tube Epithelial Cells and Ovarian Cancer Initiation from Them by a Stromal Niche
Abstract
This project is proposed to address the FY22 OCRP Area of Emphasis, Understand the basic biology and etiology of ovarian cancer initiation, progression, metastasis, recurrence, genetics and other critical events. Ovarian cancer (OC) remains the most lethal malignancy of the female reproductive system. This is largely due to the fact that most OCs are diagnosed only after the cancer has migrated into the peritoneal space of the patient. In order to improve the outcome of OC patients, one of the major challenges is to have a better understanding of the early stage of OC development, so that novel strategies can be developed to prevent OC initiation and/or to block their progression, and for early detection. Originally OC was thought to originate from epithelial cells that cover the surface of ovary. However, recent studies suggested that most OCs may actually originate from epithelial cells in the fallopian tube (FT) i.e., fallopian tube epithelial (FTE) cells; the cancer cells in the FT later migrate to the nearby ovary, eventually leading to development of ovarian cancer. Both genetic mutations and environmental/lifestyle factors contribute to risks of developing OC; for the latter, many of them are related to exposure to ovarian hormones such as estrogen. In fact, exposure to estrogen has emerged as a major factor that increases the risk of developing OC. However, how estrogen exposure contributes to the increased risk of OC initiation from its cellular origin (e.g., FTE cells) remains poorly understood. A better understanding of this should lead to novel strategies to prevent OC and/or for its early detection. To understand the cell types in FT, we performed a single cell gene expression analysis and, from this effort, we found that the main receptor for estrogen, estrogen receptor (ER) alpha, is expressed in both FTE cells and a subset of FT stromal cells, which are supporting cells for FTE cells. Interestingly, these ER+ stromal cells express many secreted factors (e.g., a growth factor referred to as insulin-like growth factor I, or IGF1) that can trigger signaling pathways in nearby cells (e.g., FTE cells), raising a possibility that these FT stromal cells represent key supporting cells (referred to as a niche) to regulate the homeostasis of the nearby FTE cells. While estrogen can regulate the normal behavior of FTE cells or promote OC initiation from FTE cells (e.g., upon exposure to too much estrogen), it is unclear whether this regulation is a direct action on ER+ FTE cells, or an indirect action on ER+ FT stromal cells, and the stromal cells then relay the signals to FTE cells. Our preliminary study as well as evidence from literature suggest the latter may be the case. We thus hypothesize that estrogen exposure activates the estrogen signaling in ER+ FT stromal cells, which causes increased proliferation, survival, or differentiation of the nearby FTE cells; this effect is in part mediated by IGF1 produced by them, which then binds to its receptor (IGF1R) on FTE cells. Excessive estrogen exposure may disrupt the balance between FTE proliferation and differentiation, e.g., by making FTE cells more proliferative and as a result, rendering them more susceptible to transformation, leading to an increased risk of OC initiation from them. To test our hypothesis, we will perform two sets of experiments, either in cultured mini-organs (referred to as organoids) formed from FTE cells from mice, or in mouse models directly. In the first set (Aim 1), we will use a genetic approach to specifically disrupt ERalpha expression in FT stromal cells, and then determine whether this manipulation leads to any change in the production of secreted factors (e.g., IGF1) from these stromal cells as well as any change in proliferation, survival, and differentiation of FTE cells. We will also analyze normal mice with exposures to different amounts of estrogen and determine whether different levels of estrogen ex
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310178
Entities
People
- Zhe Li
Organizations
- United States Army