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| Nature communications. 2020 May 29. doi: 10.1038/s41467-020-16395-2. pii: 10.1038/s41467-020-16395-2 |
| ISG15 and ISGylation is required for pancreatic cancer stem cell mitophagy and metabolic plasticity. |
| Alcalá S1, Sancho P2, Martinelli P3, Navarro D4, Pedrero C5, Martín-Hijano L6, Valle S7, Earl J8, Rodríguez-Serrano M9, Ruiz-Cañas L10, Rojas K11, Carrato A12, García-Bermejo L13, Fernández-Moreno MÁ14, Hermann PC15, Sainz B16 |
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Abstract Pancreatic cancer stem cells (PaCSCs) drive pancreatic cancer tumorigenesis, chemoresistance and metastasis. While eliminating this subpopulation of cells would theoretically result in tumor eradication, PaCSCs are extremely plastic and can successfully adapt to targeted therapies. In this study, we demonstrate that PaCSCs increase expression of interferon-stimulated gene 15 (ISG15) and protein ISGylation, which are essential for maintaining their metabolic plasticity. CRISPR-mediated ISG15 genomic editing reduces overall ISGylation, impairing PaCSCs self-renewal and their in vivo tumorigenic capacity. At the molecular level, ISG15 loss results in decreased mitochondrial ISGylation concomitant with increased accumulation of dysfunctional mitochondria, reduced oxidative phosphorylation (OXPHOS) and impaired mitophagy. Importantly, disruption in mitochondrial metabolism affects PaCSC metabolic plasticity, making them susceptible to prolonged inhibition with metformin in vivo. Thus, ISGylation is critical for optimal and efficient OXPHOS by ensuring the recycling of dysfunctional mitochondria, and when absent, a dysregulation in mitophagy occurs that negatively impacts PaCSC stemness. |
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Publikations ID: 32472071 Quelle: öffnen |
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