ORCID ID

0000-0002-6276-7528

Graduation Date

Spring 5-7-2022

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Cancer Research

First Advisor

Angie Rizzino, PhD

Abstract

The stem cell transcription factor SOX2 has been widely recognized for its critical roles during mammalian development. SOX2 expression has also been implicated in more than 20 types of human cancers. Importantly, the expression of SOX2 is regulated at multiple levels, which enables the tight regulation of SOX2 levels. Previous work from our laboratory has shown that elevating SOX2 from an inducible promoter inhibits the proliferation of several human tumor cell types. Other studies have reported that high levels of SOX2 are necessary to maintain lineage plasticity in advanced tumors. Thus, the dosage of SOX2 plays a critical role in regulating tumor cell identity and proliferation. Significantly, the downstream signaling mechanisms governing the effects of elevated SOX2 on cellular identity and proliferation are largely uncharacterized. Thus, the goal of the studies presented in this dissertation was to identify the molecular mechanisms through which high SOX2 expression regulates tumor cell identity and proliferation. In chapter 3 of this dissertation, we demonstrate that elevating SOX2 in androgen dependent prostate tumor cells modulates Hippo and Notch signaling pathways and induces a state of neuroendocrine lineage plasticity. Intriguingly, these cells remain sensitive to the antiandrogen enzalutamide despite expressing neuroendocrine markers. We also examined the mechanisms through which SOX2 elevation restricts tumor cell proliferation. We demonstrate that SOX2 elevation reversibly arrests tumor growth and that SOX2 growth-inhibited cells do not display cell cycle disruption. Consistent with this finding, SOX2 elevation downregulated a broad spectrum of the cell cycle machinery. In chapter 5 of this dissertation, we demonstrate that elevating SOX2 in multiple human tumor types decreases the expression of MYC and MYC target genes. Furthermore, we show that rescuing MYC activity in the context of elevated SOX2 induces cell death, revealing that the downregulation of MYC is critical to maintain cell survival in the presence of SOX2 elevation. Altogether, the studies presented in this dissertation provide novel insight into the molecular mechanisms through which elevated SOX2 regulates tumor cell identity and proliferation.

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