UCLA

Metabolic pathways coordinate a complex interplay between energy homeostasis, biosynthesis, signaling networks, and epigenetic processes. In many tissues, metabolism is involved in the regulation of cell fate. Furthermore, altered energy metabolism can often be leveraged to diagnose, monitor, and/or treat cancer. Lineage transitions play a pivotal role in prostate development, tumorigenesis, and treatment resistance. While the epigenome is a well-established regulator of prostate cell fate, how upstream metabolic signaling contributes to the maintenance of cell identity is poorly defined. In addition, inhibition of several metabolic pathways has been shown to antagonize the growth of prostate cancer cells. However, treatment-induced metabolic alterations and vulnerabilities have not been comprehensively elucidated. In this dissertation, I define the role of metabolism in prostate epithelial cell fate and response to therapy. In Chapter 2, I describe our refined approach to culture prostate organoids, which is used extensively in subsequent chapters. In Chapter 3, I establish pyruvate and lactate metabolism as key regulators of prostate epithelial lineage identity and response to treatment. Finally in Chapter 4, I define treatment-induced metabolic vulnerabilities in prostate cancer and identify molecular mechanisms that regulate the metabolic response to therapy. These findings yield new insights into how the modulation of metabolism can impact prostate cancer disease progression and treatment strategies.