The Tca Cycle As A Nexus Of Metabolic Vulnerabilities In Cancer

Author

Sunada KhadkaFollow

Author ORCID Identifier

0000-0002-9844-2530

Date of Graduation

5-2022

Document Type

Dissertation (PhD)

Program Affiliation

Cancer Biology

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

Ronald A. DePinho

Committee Member

Florian L. Muller

Committee Member

Frederick Lang

Committee Member

Jian Hu

Committee Member

Simona Colla

Committee Member

Michael Curran

Abstract

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.

Keywords

Cancer Metabolism, TCA cycle anaplerosis, Collateral lethality, Coenzyme A, Angiogenesis