LCN2-mediated ferroptosis resistance in tissue homeostasis and early-stage tumorigenesis of the fallopian tube epithelium.
Imaeda K., Tamura T., Nagai S., Sugihara E., Yamasaki J., Otsuki Y., Nakamura K., Takeda T., Nakamura K., Nogami Y., Tsuji K., Chiyoda T., Kisu I., Kobayashi Y., Banno K., Yamaguchi R., Sakurada K., Saya H., Aoki D., Ahmed AA., Nagano O., Masuda K., Yamagami W.
While the fallopian tube epithelium (FTE) is known to be composed of various differentiated cells such as secretory and ciliated cells, the upstream regulatory mechanisms of cell differentiation that are essential for tissue homeostasis remain under investigation. In this study, we established human FTE organoids and identified quiescent cells within the early organoid formation by observing cellular proliferation heterogeneity. We also analyzed two single-cell transcriptomic data to trace the differentiation trajectory in human FTE, and found that the gene LCN2 serves as a marker gene of early stage of the trajectory. Genetically manipulated FTE organoids indicated that LCN2 inhibits ferroptosis and promotes cell survival under oxidative stress. In addition, the FTE organoids introduced p53 dysfunction, the common genetic characteristics of high-grade serous carcinoma, showed upregulated LCN2 expression and enhanced ferroptosis resistance. This study provides insights into the LCN2-mediated protective mechanism of human FTE quiescent cells and its potential role in tumorigenesis.