Evolving Models of Ovarian Cancer: Defining the Role of PAX8 in Fallopian Tube Tumorigenesis
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CitationEmori, Megan Marie. 2015. Evolving Models of Ovarian Cancer: Defining the Role of PAX8 in Fallopian Tube Tumorigenesis. Doctoral dissertation, Harvard University, Graduate School of Arts & Sciences.
AbstractOvarian cancer is the most deadly gynecological malignancy in the US. Once thought to be a single disease arising from the ovarian surface epithelium, we now understand that it is in fact a heterogenous disease with origins across the female reproductive tract. Ovarian cancers can be broken down into type I and type II tumors. While type I tumors are typically slow growing and arise from the ovary, type II tumors are highly aggressive, particularly the most common and deadliest subtype, High Grade Serous Ovarian Cancer (HGSOC), which arises from the fallopian tube epithelium. While our understanding of the complexity of ovarian cancer has evolved significantly over the last few decades, ovarian cancer is still primarily modeled by a few historical and robust cell lines which poorly recapitulate the genetics of HGSOC patient tumors. Here we characterize less studied cell lines with high genomic fidelity to HGSOC, KURAMOCHI and OVSAHO. Through in vivo xenograft experiments, we determined that these two cell lines form more diffuse tumors which better represent the HGSOC phenotype. In vitro, these lines are tractable to a variety of standard molecular biology techniques, but only express a subset of common markers of HGSOC, including PAX8 and stabilized TP53, while others were absent. These results indicate that it is important to take both molecular and genetic relevance into consideration when selecting cell lines for laboratory studies.
PAX8 is a nuclear transcription factor critical to the development of the female reproductive tract, including the fallopian tube, and is conserved in both the adult fallopian tube and HGSOC. Recent studies have identified PAX8 as a differentially expressed, essential gene to ovarian cancer, making it a promising drug target for HGSOC. Here, we identify a subset of ovarian cancers that exhibit decreased proliferation when PAX8 expression is decreased, and determine that in KURAMOCHI cells this defect appears to be driven by cell cycle arrest. We also characterized the similarities and differences of PAX8 DNA binding and gene regulation through ChIPseq and RNAseq, respectively, in the context of the fallopian tube and HGSOC. We determined that while a small subset of PAX8 binding sites are conserved across the fallopian tube and ovarian cancer, there is a significant gain of novel binding sites in ovarian cancer that is unique to each cancer cell line. In contrast, different fallopian tube derived lines have very similar PAX8 binding sites and many of these are uniformly lost in the context of cancer. Understanding how the role of PAX8 changes from the fallopian tube to cancer is an important step to drug development targeting PAX8.
Ultimately, this body of research seeks to improve ovarian cancer modeling techniques and to better understand fallopian tube pathogenesis, leading to more effective translation of ovarian cancer research from bench to bedside.
Citable link to this pagehttp://nrs.harvard.edu/urn-3:HUL.InstRepos:23845418
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