Lineage-Specific Epigenomic Mapping of Proximal and Distal Fallopian Tube Epithelium Reveals Mesenchymal/Wnt-Driven Tumor Phenotype Diversification

High-grade serous ovarian cancer (HGSC) typically originates from the distal fallopian tube epithelium (disFTE), while the proximal epithelium (proFTE) remains less explored. Here, Using isogenic murine organoid models with common oncogenic drivers ( Tp53 ^−/− ; Kras ^mut ; Pten ^−/− ), we show that disFTE and proFTE generate distinct tumor subtypes driven by region-specific transcriptional programs. Unlike disFTE, proFTE demonstrates continuous activation of epithelial-mesenchymal transition (EMT) across wild-type, mutant organoids, and derived tumors. Additionally, mutated proFTE organoids and their tumors exhibit persistent WNT signaling activation and grow independently of WNT signals. Chromatin profiling shows that mutant proFTE maintains a distinctive epigenetic profile with promoters associated with EMT and WNT pathways. Human proFTE with BRCAmut also shows epigenetic activation of EMT- and WNT-related genes. Tumors near the uterotubal junction (UTJ)—anatomically akin to proFTE—exhibit a pronounced EMT signature, increased Vimentin+E-cadherin+ and nuclear β-catenin expression. These findings suggest proFTE-derived tumors may occupy a unique niche in gynecological malignancies, with regional identity shaping tumor phenotypes.