Unveiling The Origin of Human High-Grade Serous Ovarian Cancer Using Bulk and Single-Nucleus RNA Sequencing

Secretory cells in the fallopian tube epithelium (FTE) have been suspected to be the origin of high-grade serous "ovarian" cancer (HGSOC). However, due to the high heterogeneity of the FTE cells, the true identity of the FTE cells that are transformed into HGSOC cells and the spatiotemporal molecular events leading to carcinogenesis remain unknown. Our integrative analyses, utilizing both bulk and single-nucleus transcriptomics, revealed that the FTE cells are indeed highly heterogeneous, consisting of multiple subtypes of secretory and ciliated cells in addition to a small stem cell pool. In the adult fallopian tube, the LGR5+/PGR+ stem cells, often situated in the basal layer of the FTE, can proliferate and differentiate into OVGP1+/RNPC3+ progenitors, constituting the predominant cell types in all segments of the fallopian tube. These progenitors can quickly differentiate into ciliated or mature secretory cells to replenish the lost FTE cells when needed. Exposure to certain oncogenic factors may cause the progenitors to undergo carcinogenesis along two differentiation pathways, forming mesenchymal-like and immunoreactive cancerous cells, commonly seen in HGSOC. Key transcription factors and genetic changes in critical genes were also identified during carcinogenesis. The present study provides comprehensive cell atlases of the human fallopian tube and HGSOC and helps gain insight into the molecular events leading to the transformation of FTE progenitors into HGSCO cells. (217 words) In BriefThis report describes comprehensive cell atlases of the human fallopian tube and high-grade serous "ovarian" cancer (HGSOC), the relationships among major cell subtypes within the human fallopian tube epithelium (FTE), and the most likely pathways by which FTE progenitor cells are transformed into HGSOC cells. The data will serve as an important resource and open new avenues for further investigation into diagnostic, therapeutic, and preventive measures for FTE cell-derived HGSOC. HighlightsO_LILGR5+/PGR+ cells in human FTE represent stem cells, mostly quiescent and capable of differentiating into OVGP1+/RNPC3+ progenitors. These progenitors, in turn, differentiate into secretory and ciliated cells to maintain cellular homeostasis in the FTE. C_LIO_LIProgenitor cells, morphologically resembling secretory cells, are abundant in all segments of the fallopian tube, and those in the fimbriae are the most likely precursors of HGSOC. C_LIO_LIStem or progenitor cells can be transformed into cancerous cells following two distinct trajectories, leading to the formation of immunoreactive and mesenchymal cancer cell types common in HGSOC. C_LI