Human fallopian tube epithelial organoids with TP53 mutation recapitulate features of serous tubal intraepithelial carcinoma (STIC) -LP-WGS

Human fallopian tube epithelial organoids with TP53 mutation recapitulate features of serous tubal intraepithelial carcinoma (STIC) Judith Kraiczy, Bo Yu Gynecologic Oncology, Volume 203, 2025, Pages 198-208, ISSN 0090-8258, https://doi.org/10.1016/j.ygyno.2025.10.038. ABSTRACT Objective Serous tubal intraepithelial carcinoma (STIC) is the immediate precursor lesion for high-grade serous ovarian carcinoma (HGSOC) and harbors universal TP53 mutations. The lack of an appropriate in vitro model for STIC presents a major challenge in studying its pathogenesis. We aimed to develop a human in vitro model that mimics STIC lesions. Methods Using CRISPR-Cas9 gene editing, we generated human fallopian tube epithelial organoids with TP53 loss-of-function mutations (TP53-/- FTOs). We characterized TP53-/- FTOs on a cellular and molecular level using immunofluorescence confocal imaging, copy number variation (CNV) analysis, and RNA sequencing. Results TP53-/- FTOs recapitulated key features of STIC lesions. They exhibited increased proliferation and nuclear abnormalities, including nuclear enlargement and atypical mitotic figures. Copy number variation analysis revealed aneuploidy in some TP53-/- FTOs. Compared to unedited controls, TP53-/- FTOs demonstrated significant transcriptomic changes, including the downregulation of DNA repair genes and upregulation of epithelial-mesenchymal transition (EMT) pathways. Similar to STIC lesions, TP53-/- FTOs showed a marked reduction in ciliated cells and ciliogenesis-associated gene expression. Conclusions These findings suggest that p53 loss in FTOs promotes a proliferative and genomically unstable state that is conducive to carcinogenesis. The TP53-/- FTO model we have generated provides a valuable tool for studying early events in ovarian carcinogenesis and for developing new strategies for the early detection and prevention of ovarian cancer. Overall design: Low-pass whole genome sequencing of human fallopian tube organoids with TP53 loss-of-function mutations (TP53-/- FTOs) and controls, as well as longitudinal samples of these organoids at a later passage