Hormone regulation of fallopian tube inflammation and cancer initiation via a stromal niche

About This Grant

Ovarian cancer (OC) is the most lethal malignancy of the female reproductive system, largely due to late diagnosis and widespread peritoneal metastasis at presentation. Improving patient outcomes requires a deeper understanding of early OC development. A major paradigm shift has identified fallopian tube epithelial (FTE) cells, rather than ovarian surface epithelium, as the main cellular origin of serous OC. Both genetic (e.g., BRCA1/2 mutations) and environmental factors influence OC risk. Among the latter, prolonged estrogen exposure is a known risk factor, though the underlying mechanisms remain unclear. Insight into this could have implications for OC risk reduction, prevention, and early detection. In preliminary studies, we identified a population of Esr1+ stromal cells in the fallopian tube (FT) that express many secreted factor genes. Deletion of Esr1 in these cells led to smaller FTs in mutant mice compared to wild-type (WT) controls. Transcriptomic profiling showed reduced expression of inflammation- and extracellular matrix (ECM)-related genes in Esr1- null stromal cells. Coupled with recent findings linking estrogen-driven hormonal cycles to FT inflammation and fibrosis, we hypothesize that Esr1+ FT stromal cells form a hormone-responsive niche that relays estrogen signals to adjacent FTE cells via inflammatory cytokines and other secreted factors to regulate their proliferation and differentiation. Disruption of this interaction through aberrant estrogen signaling may create an inflammatory microenvironment that impairs FTE homeostasis and promotes OC initiation. To test this hypothesis, we propose three Specific Aims. Aim 1 will use conditional Esr1 deletion and hormonal perturbation approaches to assess whether estrogen signaling in FT stromal cells drives chronic inflammation, with integrated single-cell profiling to investigate inflammatory memory upon aging. Aim 2 will employ several OC mouse models with an FTE origin to test whether a detrimental stromal niche caused by aberrant estrogen signaling promotes OC development in a stromal Esr1-dependent manner. Aim 3 will examine whether Esr1+ FT stromal cells are precursors to high-risk mesenchymal stem cells (hrMSCs) found in human serous OC precursor lesions and whether estrogen signaling contributes to their formation and function during serous OC initiation or progression. As it is not feasible to longitudinally study early transformation of FTE cells or manipulate estrogen-driven stromal-epithelial interactions directly in humans, mouse models are necessary for this stage of investigation to enable controlled in vivo genetic and hormonal perturbations that cannot be fully recapitulated in vitro. Overall, this project is expected to uncover how estrogen-driven changes in the FT stromal microenvironment contribute to early OC development, offering new insights into prevention strategies. By identifying key stromal-epithelial interactions and their role in cancer initiation, the findings could inform targeted interventions to reduce OC risk and improve early detection in patients.