Author ORCID Identifier
Date of Graduation
Doctor of Philosophy (PhD)
Ronald A. DePinho
Florian L. Muller
Uncontrolled proliferation of cancer cells necessitates rewiring of metabolic pathways to meet biosynthetic and bioenergetic demands of proliferation and fortify redox homeostasis. An increasing body of literature suggests that mitochondrial metabolism (tricarboxylic acid cycle (TCA) and oxidative phosphorylation) is imperative for cancer cell growth and proliferation. The scope of the works presented in this dissertation is to explore the importance of mitochondrial metabolism, and primarily the TCA cycle—the anabolic factory of cancer cells and leverage it as a targetable vulnerability in cancer. Cancer cells consume anabolic nutrients that are used to generate biosynthetic precursors in the TCA cycle. Continuous efflux of carbon atoms from the TCA cycle for biosynthetic and catabolic oxidative reactions requires carbon atoms to be replenished by a process called anaplerosis. The work in this thesis shows that impinging on TCA cycle anaplerosis, either by impairing the breakdown of nutrients (glycolysis/glutaminolysis inhibition), or by restricting the import of blood-borne nutrients (angiogenesis inhibition), or by targeting coenzyme biosynthesis (acetyl-CoA for TCA cycle), can selectively impair cancer cell viability in vitro and in intracranial growth of tumors in vivo. Collectively, the work described herein establishes the TCA cycle as a promising targetable vulnerability in cancer.
Cancer Metabolism, TCA cycle anaplerosis, Collateral lethality, Coenzyme A, Angiogenesis
Available for download on Tuesday, May 09, 2023