Description:

BMG Faculty Candidate Seminar
Department of Biochemistry and Molecular Genetics

“From Genotype to Immune Evasion: Membrane Lipid and Mitochondrial Vulnerabilities in Cancer”

Gokhan Unlu, PhD
Damon Runyon Postdoctoral Fellow
Laboratory of Metabolic Regulation and Genetics (Birsoy Lab)
The Rockefeller University, New York, NY

Abstract:

Although oncogenic alterations influence tumor metabolism, how they impose distinct metabolic programs within a shared tissue context remains poorly defined. Here, we developed a rapid mitochondrial profiling platform to compare metabolites and proteins in genetic models of primary liver cancer (PLC). Analyses of six genetically distinct PLCs revealed that mitochondrial energy metabolism is largely dictated by oncogene identity. Kras-driven tumors required creatine metabolism to buffer energy demands during early tumorigenesis, whereas c-MYC-driven tumors relied on oxidative phosphorylation. Among c-MYC-driven PLCs, Pten-deficient tumors accumulated mitochondrial phosphoethanolamine, a precursor for phosphatidylethanolamine (PE) synthesis. Inhibition of PE synthesis selectively impaired the growth of Pten-deficient tumors and extended survival, in part through enhanced infiltration of CD8⁺ T cells and sensitization to TNFα-mediated cytotoxicity. Mechanistically, loss of PE elevated surface TNF receptor 2 (TNFR2), promoting TNFα signaling and pro-inflammatory response. These findings uncover genotype-specific mitochondrial metabolic liabilities and establish PE synthesis as a tumor-intrinsic mechanism of immune evasion in PLC.

Hosts: Drs. Ali Shilatifard, Chairman, and Issan Ben-Sahra, Associate Professor, Department of Biochemistry and Molecular Genetics