Unlu, Gokhan, Millet, Alon, Wangdu, Khando, Donné, Romain, Erdal, Ranya, DelGaudio, Nicole L, Uygur, Beste, Shah, Vyom, Cho, Kevin, Fecke, Antonia, Cansiz, Feyza, Tarcan, Zeynep Cagla, Isay-Del Viscio, Michael, Kilic, Ece, Kurth, Isabel, Molina, Henrik, Sickmann, Albert, Basturk, Olca, Patti, Gary, Beyaz, Semir, Smith, Karl W, Lujambio, Amaia, Tasdogan, Alpaslan, Tavazoie, Sohail F, Birsoy, Kıvanç (September 2025) Tumor Genotype Dictates Mitochondrial and Immune Vulnerabilities in Liver Cancer. bioRxiv. ISSN 2692-8205 (Submitted)
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.
| Item Type: | Paper |
|---|---|
| Subjects: | diseases & disorders > cancer diseases & disorders diseases & disorders > cancer > cancer types > liver cancer diseases & disorders > cancer > cancer types |
| CSHL Authors: | |
| Communities: | CSHL labs > Beyaz lab CSHL labs > Meyer Lab |
| SWORD Depositor: | CSHL Elements |
| Depositing User: | CSHL Elements |
| Date: | 11 September 2025 |
| Date Deposited: | 08 Jul 2026 16:20 |
| Last Modified: | 08 Jul 2026 16:20 |
| PMCID: | PMC12440024 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/42264 |
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