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COMPARISONS OF THE PROXIMAL AND DISTAL REGIONS OF THE FALLOPIAN TUBE

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Abstract

Ovarian/extra-uterine high-grade serous carcinoma (HGSC) is the most common and most lethal gynecological malignancy in the United States. There is now a substantial body of evidence indicating that many (and likely more than half) of HGSCs originate in the Fallopian tube. Moreover, serous tubal intraepithelial carcinomas (STICs), the putative precursor lesions to HGSC are more frequently found in the distal (closer to the ovary) Fallopian tube's epithelium (TE). This has led many to wonder what factors might be influencing the distal region of the TE to give rise to HGSC. Here, comparisons between the proximal region of the Fallopian tube (which is farther from the ovary, and evidently less inclined towards malignant transformation) and the distal region of the Fallopian tube are used to identify factors which may be promoting malignant transformation in the TE. Adult tissue stem cells (SCs) are frequently involved in malignant transformation. Previous studies suggests that the proximal and distal TE differ in the number and properties of their SCs. Inflammation associated with ovulation is also suspected of being involved in ovarian cancer's development. However, data pertaining to the human TE is sparse, and genomic data is particularly scarce. Accordingly, we isolated populations enriched for stem and differentiated epithelial cells from both proximal and distal anatomically normal Fallopian tube fragments. We then performed organoid and bulk mRNA-seq analyses aimed at identifying differences between the proximal and distal TE. Our analysis identifies heightened inflammatory signaling in distal differentiated cell enriched populations. Additionally, we observe expression of gene sets associated with HGSC and malignant disease in SC enriched populations. Applying bulk mRNA-seq to epithelial cell enabled us to identify broad patterns of gene expression across the TE. While valuable, this approach precludes analyses focused on the biology of non-epithelial cells. The use of bulk mRNA-seq also presents challenges to identifying patterns of gene expression characteristic of specific cell types. Therefore, we carried out single cell mRNA-seq using the proximal and distal Fallopian tube fragments of four more individuals, supplemented by published single cell distal TE and HGSC data. Consistent with our earlier findings, distal secretory epithelial cells display increased expression of several genes associated with NF-_B signaling.

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182 pages

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2020-12

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Union Local

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Nikitin, Alexander

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Kurpios, Natasza
Danko, Charles G.

Degree Discipline

Genetics, Genomics and Development

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Ph. D., Genetics, Genomics and Development

Degree Level

Doctor of Philosophy

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Government Document

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Attribution-NonCommercial-NoDerivatives 4.0 International

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dissertation or thesis

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