Ovarian cancer (OC) is one of the most lethal gynecologic malignancies, with a 5-year survival rate of merely 50 % [1]. Due to a lack of early detection methods, 70 % of OC are diagnosed in late stages (stage III-IV) when the prognosis is poor [1].The most common OC subtype, high-grade serous ovarian carcinoma (HGSOC), accounts for ∼70 % of OC and has the worst prognosis [1]. The majority of HGSOC are thought to originate from cells of the fallopian tube epithelium (FTE) [[2], [3], [4], [5]]. Serous tubal intraepithelial carcinoma (STIC) has been recognized as an immediate precursor of HGSOC [[6], [7], [8]]. STIC lesions are defined as localized epithelial regions consisting of non-ciliated cells with altered p53 immunostaining due to TP53 gene mutations, combined with morphological criteria such as nuclear enlargement, loss of cell polarity and mitotic figures [5,8,9]. Approximately 70-80 % of STIC lesions exhibit a high labeling index for cell proliferation markers like Ki67, indicating a proliferative STIC subtype. Conversely, other lesions contain few proliferating cells, representing a dormant subtype [10,11]. Various types of TP53 mutations exist in STIC lesions [12,13]. In missense TP53 mutations, faulty p53 protein accumulates and manifests as strong p53 immunohistochemical staining. In contrast, 12-38 % of STIC lesions exhibit loss-of-function mutations, which include nonsense or frameshift mutations, resulting in absence of p53 staining on immunohistochemistry [10,12,14]. STIC lesions, especially when adjacent to HGSOC, display increased gene expression of immune effectors, such as the interferon pathway and epithelial-mesenchymal transition (EMT) [15].

Since the identification of STIC lesions requires histopathological examination of fixed tissue, no live STIC cells or STIC cell lines are available for research, leaving gaps in our ability to study oncogenic factors and molecular processes involved in the transformation from STIC to HGSOC. To overcome these limitations, other models are needed to mimic STIC lesions in vitro. Organoids have emerged as powerful in vitro models for many cancers, capitalizing on their long-term viability and consistent recapitulation of tissue-specific characteristics [16]. Patient-derived FTE organoids (FTOs) bear a striking resemblance to FTE tissue characteristics in vivo, forming a luminal structure enveloped by a basement membrane. The single-layer columnar epithelium of FTOs consists of secretory and ciliated cells [17,18]. Their ability to self-renew and maintain their original cellular and molecular attributes over long-term culture makes them an ideal model system for translational research. FTOs derived from patients with OC can recapitulate their specific genetics and pharmalogical responses [[19], [20], [21], [22], [23]]. However, there is no human FTO model that can recapitulate the features of STIC lesions in vitro.

To address the unmet need of a human in vitro model that recapitulates the features of STIC lesions, we generated human FTE-derived organoids with TP53 loss-of-function mutations (TP53-/- FTOs) by CRISPR-Cas9 gene editing. TP53-/- FTOs demonstrate various morphological and genomic features that mimic STIC lesions.