ISG15 and ISGylation is required for pancreatic cancer stem cell mitophagy and metabolic plasticity
Open Access
- 29 May 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Communications
- Vol. 11 (1), 2682
- https://doi.org/10.1038/s41467-020-16395-2
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.Funding Information
- Ministry of Economy and Competitiveness | Instituto de Salud Carlos III (CP16/00121, PI18/00267, PI15/01507, PI18/00757)
- Austrian Science Fund (FWF-B27361)
- Fundación Científica Asociación Española Contra el Cáncer (GC16173694BARB, GC16173694BARB)
- Deutsche Krebshilfe (111746)
- Deutsche Forschungsgemeinschaft (CRC 1279)
- Ministerio de Economía y Competitividad (RYC-2012-12104)
- Concern Foundation (n/a)
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