Graduation Date

Fall 12-16-2016

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Cancer Research

First Advisor

Angie Rizzino, Ph.D.

Abstract

The transcription factor SOX2 is widely recognized for its critical roles during mammalian embryogenesis. SOX2 has also been examined in cancer; and it has been implicated in the growth, tumorigenicity, drug resistance, or metastasis of over 20 different cancers, including cancers of the brain and pancreas. Thus, we hypothesized that SOX2 is a major player in cancer and may be a potential therapeutic target; however, the effects of SOX2 on the many facets of human cancer have only begun to be explored. Recently, efforts to understand the mechanisms by which SOX2 mediates its effects have explored SOX2 protein-protein interaction landscapes in a number of cellular systems. Previous studies in our laboratory identified proteins, like the RNA-binding protein Musashi2 (Msi2), which interact with SOX2 in multiple cell types, including embryonic stem cells and brain tumor cells. We hypothesized that proteins that interact with SOX2 in multiple cell types are likely to be necessary for the continued growth and function of these cells. The studies presented in this dissertation demonstrate that ESC require Msi2 to maintain self-renewal and pluripotency; and that MSI2 is also required to support the growth and survival of DAOY, U87, and U118 brain tumor cell lines. This dissertation also examined the roles of SOX2 in pancreatic adenocarcinoma (PDAC). Multiple PDAC cell lines were engineered for either inducible overexpression of SOX2 or inducible knockdown of SOX2. Through in vitro growth and tumorigenicity studies with these inducible PDAC cell lines, we determined that SOX2 functions as a biphasic molecular rheostat in PDAC. Furthermore, we determined that inducible elevation of SOX2 in PDAC cells reduces the growth inhibitory effects of MEK and AKT inhibitors, while the inducible knockdown of SOX2 enhanced growth inhibition in the presence of these inhibitors. Altogether, the work presented in this dissertation extends and strengthens our knowledge of SOX2 and its function as a master regulator in multiple cell types, and provides useful platforms for the continued study of these highly deadly malignancies.

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