Graduation Date

Winter 12-16-2022

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Cancer Research

First Advisor

Nicholas Woods

Second Advisor

Robert Lewis

Third Advisor

Kurt Fisher

Fourth Advisor

Kathryn Cooper

Abstract

Advancements in next-generation sequencing technologies have made omics technologies accessible to more researchers and large omics datasets are becoming more common in biological research. Omics technologies, including genomics, transcriptomics, proteomics, and metabolomics, have been pivotal in our current understanding of development, how developmental defects can lead to cancer, and importantly, our approach to chemotherapeutic treatment for cancer patients. This dissertation describes two projects using both experimental and omics technologies to investigate molecular mechanisms in Pancreatic Ductal Adenocarcinoma (PDAC) and mammary gland development.

Pancreatic Ductal Adenocarcinoma (PDAC) is a devastating disease that is difficult to treat with current therapies. Subtyping PDAC based on their underlying molecular features is hoped to stratify patients for individualize treatment and better therapeutic outcomes. Recent work suggests modifiable risk factors influence subtype development in patients, for example alcohol use. However, the underlying mechanisms of alcohol use on subtype development is unclear. The first project in this dissertation focuses on alcohol use in KRAS-mutated pancreatic cells, using both experimental and omics technologies to investigate alcohol’s influence in subtype development.

CTD phosphatase 1 (Ctdp1) is a phosphatase that regulates phosphorylation of the C-terminal domain of the RNA polymerase II, a major polymerase essential for transcribing protein-coding mRNAs. Recent work from our lab suggests Ctdp1 involvement in functional mammary gland development, milk production and prevention of cancer. Moreover, Ctdp1 may possess stem-like functions. The second part of this dissertation describes the impact loss of Ctdp1 has on mammary epithelial cells. Using single-cell RNA sequencing, we show Ctdp1 loss prevents basal cell development through mTORC2 dephosphorylation.

Comments

2022 Copyright, the authors

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