The role of oncogenic c-myc in reprogramming mitochondrial metabolism

• Applicant: Dr. Ji-Young Kim
• Subject Area: Cell Biology ; Hematology, Oncology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 546565816

The Myc proto-oncogenes comprise a family of transcription factors that are among the most commonly activated oncoproteins in human cancer. Both MYC-driven tumors and tumors with other oncogenic drivers, such as KRAS, have been shown to depend on enhanced MYC activity for growth. At the same time, MYC has been notoriously difficult to target therapeutically. Since metabolic dysregulation is a hallmark of oncogenic MYC activation, these vulnerabilities may present viable new targets to exploit metabolic synthetic lethality. MYC-driven cancer cells rely on glutamine for both oxidative and reductive processes, necessary for ATP generation and the production of mitochondrial intermediates required for anabolic growth, respectively. These biosynthetic intermediates include proline and ornithine. The enzyme P5CS represents a link between these oxidative and reductive processes in mitochondrial glutamine metabolism. Compelling preliminary results from the Thompson laboratory demonstrate that mitochondrial sequestration into two metabolically distinct subpopulations - one characterized by complex V for oxidative functions and the other by P5CS filaments for reductive biosynthesis, supported by mitochondrial fusion-fission processes - is required to sustain proline and ornithine production during cell proliferation. This project will investigate these processes in MYC-driven cancers. Functional mitochondrial segregation will be examined under both nutrient-rich and various stress conditions to investigate the effects of bioenergetic stress and hypoxia on oxidative phosphorylation (OXPHOS) and reductive mitochondrial biosynthesis in human MYC-driven cancer cell lines. Metabolic tracing with [U-13C] glutamine will also be performed to monitor glutamine metabolism. The in-vivo relevance of this phenomenon of mitochondrial segregation will be verified by confirming mitochondrial segregation in two ways: using a xenograft assay, in which human cancer cell lines subcutaneously injected into immune-deficient mice will be resected, and through analysis of patient tumor samples. Furthermore, previous studies have shown that depletion of mitochondrial NADPH, a required cofactor for reductive metabolic processes, results in proline auxotrophy and limits proliferation in cancer cells. Mitochondrial NADP(H) is derived from NAD(H) in a compartment-specific manner by the enzyme NADK2. Therefore, NADK2 will be explored as a potential metabolic vulnerability in MYC-driven cancers. For instance, CRISPR/Cas9-mediated NADK2-knockout cell lines derived from the human cancer cell lines will be injected subcutaneously into immune-deficient mice to measure tumor growth. Together, the results of these experiments will provide further insights into the nature and cellular function of mitochondrial fission-fusion processes and explore NADK2 as a metabolic vulnerability in MYC-driven cancers, which have a high unmet clinical need.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Professor Dr. Craig B. Thompson