Department of Biomedical Sciences, Cornell University, Ithaca, NY, USA.
Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY, USA.
Nat Commun. 2024 Oct 5;15(1):8641. doi: 10.1038/s41467-024-52984-1.
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 cancer-prone cell state and point to pre-ciliation mechanisms as diagnostic and therapeutic targets.
子宫（输卵管）的远端区域通常与高级别浆液性癌（HGSC）相关，HGSC 是卵巢或子宫外癌症的主要且最具侵袭性的形式。成人输卵管上皮（TE）的特定细胞状态和谱系动力学仍了解不足，这阻碍了确定 HGSC 起源细胞的努力。在这里，我们报告了对小鼠子宫管的细胞类型和状态的全面普查。我们表明，表达干细胞/祖细胞标记物 Slc1a3 的远端 TE 细胞可以分化为分泌细胞（Ovgp1+）和纤毛细胞（Fam183b+）。Trp53 和 Rb1 的失活，其途径在 HGSC 中通常改变，导致靶向 Slc1a3+细胞通过细胞凋亡消除，从而防止其恶性转化。相比之下，预纤毛细胞（Krt5+，Prom1+，Trp73+）仍然具有致癌倾向，并导致浆液性输卵管上皮内癌和明显的 HGSC。这些发现将过渡前纤毛细胞确定为一种具有致癌倾向的细胞状态，并指出前纤毛发生机制是诊断和治疗的靶点。
