Date of Award

8-2023

Document Type

Campus Access Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biology/Molecular, Cellular, and Organismal Biology

First Advisor

Shailja Pathania

Second Advisor

Jill A. Macoska

Third Advisor

Changmeng Cai

Abstract

Germline or somatic mutation(s) in BRCA1 is associated with a 40-50% lifetime risk of developing high grade serous ovarian cancer (HGSOC), which is one of the most aggressive subtypes of epithelial ovarian cancers. To design better therapeutic options for women with ovarian cancer, it is vital to understand the cell-of-origin and identify molecular factors that drive cells to tumorigenesis. Based on mouse models, transcriptomic profiles, and organoid studies, both ovarian surface epithelium (OSE) and fallopian tube epithelium (FTE) can be the cell-of-origin of HGSOC. However, identification of precancerous lesions in FTEs indicate that FTEs are more prone to tumorigenesis suggesting that they have higher potential of being the cell-of-origin of HGSOC. Given that majority of HGSOCs carry mutations in DNA damage repair proteins, I set out to determine whether DNA damage differences between OSE and FTE and defective DNA damage repair in one cell type more than the other could contribute towards HGSOC. To address this question, I used isogenic mouse ovarian surface and fallopian tube epithelial lines, human ovarian surface and fallopian tube epithelial lines, and fallopian and ovarian tissue sections from BRCA1 wildtype and BRCA1 mutation carrying women. With this work I hope to provide the mechanistic understanding for why fallopian tube epithelial cells are the prime cell of origin for HGSOC and identify potential early biomarkers that can provide support to opportunistic salpingectomy (OS) as a risk reducing surgery for BRCA mutation carriers.

Comments

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