Pre-ciliated tubal epithelial cells are prone to initiation of high-grade serous ovarian carcinoma. Pre-ciliated tubal epithelial cells are prone to initiation of high-grade serous ovarian carcinoma

The distal region of the uterine (Fallopian) tube is commonly associated with high-grade serous carcinoma (HGSC), the predominant and most aggressive form of ovarian or extra-uterine cancer. Specific cell states and lineage dynamics of the adult tubal epithelium (TE) remain insufficiently understood, hindering efforts to determine the cell of origin for HGSC. Here, we report a comprehensive census of cell types and states of the mouse uterine tube. We show that distal TE cells expressing the stem/progenitor cell marker Slc1a3 can differentiate into both secretory (Ovgp1+) and ciliated (Fam183b+) cells. Inactivation of Trp53 and Rb1, whose pathways are commonly altered in HGSC, leads to elimination of targeted Slc1a3+ cells by apoptosis, thereby preventing their malignant transformation. In contrast, pre-ciliated cells (Krt5+, Prom1+, Trp73+) remain cancer-prone and give rise to serous tubal intraepithelial carcinomas and overt HGSC. These findings identify transitional pre-ciliated cells as a previously unrecognized cancer-prone cell state and point to pre-ciliation mechanisms as novel diagnostic and therapeutic targets. Overall design: Mouse uterine tubes were split into distal and proximal sections for single cell expression and transcriptome analysis. We isolated tubes from groups of C57BL6 adult estrous female mice to characterize the cell states present.

输卵管远端通常与高级别浆液性癌（high-grade serous carcinoma, HGSC）相关，后者是卵巢或子宫外癌中占比最高且侵袭性最强的亚型。目前学界对成年输卵管上皮（tubal epithelium, TE）的特定细胞状态与谱系动态仍缺乏足够认识，这阻碍了确定HGSC起源细胞的研究工作。本研究对小鼠输卵管的细胞类型与状态完成了全面普查，结果显示：表达干细胞/祖细胞标志物Slc1a3的远端TE细胞可分化为分泌型（Ovgp1+）与纤毛型（Fam183b+）细胞。Trp53与Rb1通路在HGSC中常发生异常改变，二者的失活会通过凋亡作用清除靶向的Slc1a3+细胞，进而阻止其恶性转化。与之相反，前纤毛细胞（Krt5+、Prom1+、Trp73+）仍具有较高的癌变易感性，可进展为浆液性输卵管上皮内癌及显性HGSC。本研究将过渡性前纤毛细胞鉴定为此前未被认知的易癌变细胞状态，并提示纤毛发生前机制可作为新型诊断与治疗靶点。总体实验设计：将小鼠输卵管分为远端与近端区段，进行单细胞表达及转录组分析。本研究从多组C57BL6成年动情期雌性小鼠体内分离输卵管，以表征其存在的各类细胞状态。