Date of Award

2026

Degree Type

Thesis

Degree Name

Master of Science (MS)

Department

Biological Science

First Advisor

Ali Vaziri-Gohar

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers, with a five-year survival rate of 13%. Most tumors are resistant to chemotherapy and immunotherapy. Consequently, there is a dire need for new ways to treat PDAC patients. One major reason that PDAC is so hard to treat is because of its unique tumor microenvironment. The tumor is comprised of very dense stroma. This results in vasculature collapse and poor perfusion to the tumor, subsequently resulting in a nutrient deprived microenvironment. As a result of this, the PDAC cells will alter their metabolic profiles to one that is much more plastic and dynamic and better able to adapt and survive in those nutrient deprived conditions. One of the main metabolic adaptations that occurs is an upregulation in mitochondrial metabolism through the use of anaplerotic substrates. Therefore, targeting these metabolic dependencies has the potential to overcome resistance mechanisms and sensitize cells to treatment. This study investigates the gamma glutamyl cycle as a novel metabolic dependency of PDAC. Specifically, gamma glutamyl cyclotransferase (GGCT), a key enzyme in the cycle, is identified to supply glutamate anaplerotically to the mitochondria in order to help sustain the upregulated mitochondrial metabolism in PDAC. This thesis demonstrates that GGCT is upregulated in PDAC patients and cell lines and is highly expressed under the nutrient deprived conditions seen in PDAC tumor microenvironments. Furthermore, metabolic profiling such as oxygen consumption rate, ATP assays, mitochondrial biogenesis measurements, TCA metabolite analysis by gas chromatography mass spectrometry, and reactive oxygen species measurements provide substantial evidence that GGCT does in fact support mitochondrial metabolism in PDAC through its production of glutamate. Moreover, this thesis demonstrates that targeting GGCT may be a novel therapeutic strategy for PDAC with the potential to improve clinical outcomes.

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