Single-cell transcriptomics identifies gene expression networks driving differentiation and tumorigenesis in the human fallopian tube

SummaryThe human fallopian tube harbors the cell-of-origin for the majority of high-grade serous ‘ovarian’ cancers (HGSCs), but its cellular composition, particularly the epithelial component, is poorly characterized. We performed single-cell transcriptomic profiling in 12 primary fallopian specimens from 8 patients, analyzing around 53,000 individual cells to map the major immune, fibroblastic and epithelial cell types present in this organ. We identified 10 epithelial sub-populations, characterized by diverse transcriptional programs including SOX17 (enriched in secretory epithelial cells), TTF3 and RFX3 (enriched in ciliated cells) and NR2F2 (enriched in early, partially differentiated secretory cells). Based on transcriptional signatures, we reconstructed a trajectory whereby secretory cells differentiate into ciliated cells via a RUNX3high intermediate. Computational deconvolution of the cellular composition of advanced HGSCs based on epithelial subset signatures identified the ‘early secretory’ population as a likely precursor state for the majority of HGSCs. The signature of this rare population of cells comprised both epithelial (EPCAM, KRT) and mesenchymal (THY1, ACTA2) features, and was enriched in mesenchymal-type HGSCs (P = 6.7 × 10−27), a group known to have particularly poor prognoses. This cellular and molecular compendium of the human fallopian tube in cancer-free women is expected to advance our understanding of the earliest stages of fallopian epithelial neoplasia.

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Modulation of leukemia inhibitory factor gene expression and protein biosynthesis in the human fallopian tube

American Journal of Obstetrics and Gynecology ◽

10.1016/s0002-9378(96)70114-x ◽

1996 ◽

Vol 175 (6) ◽

pp. 1611-1619 ◽

Cited By ~ 37

Author(s):

Martin D. Keltz ◽

Erkut Attar ◽

Sumati Buradagunta ◽

David L. Olive ◽

Harvey J. Kliman ◽

...

Keyword(s):

Gene Expression ◽

Fallopian Tube ◽

Leukemia Inhibitory Factor ◽

Protein Biosynthesis ◽

Inhibitory Factor ◽

Factor Gene ◽

Human Fallopian Tube

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HOXA10 gene expression in human fallopian tube and ectopic pregnancy

American Journal of Obstetrics and Gynecology ◽

10.1016/j.ajog.2004.01.066 ◽

2004 ◽

Vol 190 (5) ◽

pp. 1404-1406 ◽

Cited By ~ 24

Author(s):

Sana M Salih ◽

Hugh S Taylor

Keyword(s):

Gene Expression ◽

Ectopic Pregnancy ◽

Fallopian Tube ◽

Human Fallopian Tube

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Exposure of human fallopian tube epithelium to elevated testosterone results in alteration of cilia gene expression and beating

Human Reproduction ◽

10.1093/humrep/deaa157 ◽

2020 ◽

Vol 35 (9) ◽

pp. 2086-2096 ◽

Cited By ~ 1

Author(s):

Tia Jackson-Bey ◽

José Colina ◽

Brett C Isenberg ◽

Jonathan Coppeta ◽

Margrit Urbanek ◽

...

Keyword(s):

Gene Expression ◽

Fallopian Tube ◽

Microfluidic Devices ◽

Gynecologic Surgery ◽

Additional Contribution ◽

Testosterone Concentration ◽

Ciliary Beating ◽

Human Fallopian Tube ◽

The Impact ◽

Beating Frequency

Abstract STUDY QUESTION How does exposure to a testosterone rich environment affect the function and gene expression of human fallopian tube epithelium (hFTE)? SUMMARY ANSWER Elevated testosterone level alters several gene transcripts that regulate cilia expression and negatively impacts the rate of cilia beating. WHAT IS KNOWN ALREADY The presence of estrogen in the follicular phase of the menstrual cycle increases the human fallopian tube ciliary beating frequency. The luteal phase, triggered by ovulation and increasing progesterone, is marked by a decrease in ciliary beating. Women with polycystic ovarian syndrome (PCOS) may have twice the serum level of testosterone than ovulatory women. To date, the effect of elevated androgens on the function of the human fallopian tube is not well-understood. We chose to examine the impact of elevated testosterone on hFTE. STUDY DESIGN, SIZE, DURATION A prospective basic science study of human fallopian tube specimens from reproductive-aged women undergoing benign gynecologic surgery was performed. Fallopian tube removal at a large US academic center was collected and provided to us to continue with epithelium isolation and culturing. A total of 12 patients were analyzed in the study. PARTICIPANTS/MATERIALS, SETTING, METHODS Fallopian tube epithelium was isolated and exposed to two different conditions: normal with low testosterone concentration of 0.8 nM and PCOS-like, with high testosterone concentration of 2 nM. The study was conducted in both static and dynamic conditions in microfluidic devices for a total of 14 days, after which the tissue was collected for processing including RNA extraction, quantitative PCR and immunohistochemistry. After the first 7 days of each experiment, a sample of tissue from each condition was imaged to quantify cilia beating frequency. MAIN RESULTS AND THE ROLE OF CHANCE hFTE exposed to the 2 nM testosterone displayed slower cilia beating, inhibited estrogen signaling and decreased expression of the ciliary marker FOXJ1 when compared to stimulation with 0.8 nM testosterone. LARGE SCALE DATA N/A. LIMITATIONS, REASONS FOR CAUTION The in vivo response to elevated testosterone may differ from in vitro studies. RNA amount was limited from tissue cultured in the microfluidic devices as compared to static culture. WIDER IMPLICATIONS OF THE FINDINGS Understanding elevated testosterone in tubal function may explain an additional contribution to subfertility in women with PCOS and other hyper-androgen disorders, aside from oligo-ovulation. Furthermore, this adds to the body of literature of fallopian tube function using a microfluidic device. STUDY FUNDING/COMPETING INTEREST(S) NIH grants: UH3 ES029073 and R01 CA240301. There are no competing interests.

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