Abstract

The fallopian tube, connecting the uterus with the ovary, is a dynamic organ that undergoes cyclical changes and is the site of several diseases, including serous cancer. Here, we use single-cell technologies to construct a comprehensive cell map of healthy pre-menopausal fallopian tubes, capturing the impact of the menstrual cycle and menopause on different fallopian tube cells at the molecular level. The comparative analysis between pre- and post-menopausal fallopian tubes reveals substantial shifts in cellular abundance and gene expression patterns, highlighting the physiological changes associated with menopause. Further investigations into menstrual cycle phases illuminate distinct molecular states in secretory epithelial cells caused by hormonal fluctuations. The markers we identified characterizing secretory epithelial cells provide a valuable tool for classifying ovarian cancer subtypes.

Graphical summary Graphical summary of results. During the proliferative phase (estrogenhigh) of the menstrual cycle, SE2 cells (OVGP1+) dominate the fallopian tube (FT) epithelium, while SE1 cells (OVGP1-) dominate the epithelium during the secretory phase. Though estrogen levels decrease during menopause, SE post-cells (OVGP1+, CXCL2+) make up most of the FT epithelium.

Competing Interest Statement

E.L. receives research funding to study ovarian cancer from Arsenal Bioscience and AbbVie through the University of Chicago unrelated to this work. All other authors declare no other competing interest.

Funding Statement

We thank the women who donated the tissues and the surgeons that helped make this study possible. We also thank the Human Tissue Resource Center, the Genomics Facility, and the patients that kindly donated tissues for this study. Grant funding: This work is supported by the Chan Zuckerberg Initiative (to E.L., O.B., M.W., M.C.). M.C. is supported by the NIH (R01 GM126553 and R01 HG011883), the National Science Foundation (NSF 2016307), and the Sloan Research Fellowship Program. A.B. is supported by NIH DP2AI158157. E.L. is supported by R35CA264619, RO1CA211916, RO1CA237029, the Ovarian Cancer Research Alliance (OCRA), and Bears Care the charitable beneficiary of the Chicago Bears Football Club.

Author Declarations

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

All procedures were conducted under the approval of the institutional Review Board at the University of Chicago.

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Data Availability

De-identified human single-cell RNA and ATAC sequencing data have been deposited at CELLxGENE and at the European Genome-Phenome Archive (EGA). They are publicly available as of the date of publication. The link to the data is listed in the key resource table.

AbbreviationsAampullaB/PB and plasma B cellsCEciliated epithelial cellsEMTepithelial to mesenchymal transitionENendothelial cellsFfimbriaeFTfallopian tubeFTECfallopian tube epithelial cellsFTSCfallopian tube stromal cellsGWASgenome-wide association studiesH&Ehematoxylin and eosinHGSChigh-grade serous cancerIisthmusIMimmune cellsLElymphatic endothelial cellsMAmast cellsMNmonocytesMPmacrophagesP/Vpericytes and vascular smooth muscle cellsscRNA-seqsingle-cell RNA sequencingscATAC-seqsingle-cell assay on transposase-accessible chromatinSEsecretory epithelial cellsSMsmooth muscle cellsSTstromal cellsTCGAThe Cancer Genome AtlasT/NKT and NK cellsTFtranscription factorsSASPsenescence-associated secretory phenotype