ISG15 and ISGylation is required for pancreatic cancer stem cell mitophagy and metabolic plasticity

Alcalá, S. ; Sancho, P. ; Martinelli, P. ; Navarro, D. ; Pedrero, C. ; Martín-Hijano, L. ; Valle, S. ; Earl, J. ; Rodríguez-Serrano, M. ; Ruiz-Cañas, L. ; Rojas, K. ; Carrato, A. ; García-Bermejo, L. ; Fernández-Moreno, M.Á. ; Hermann, P.C. ; Sainz, B. ; , Jr.

Resumen: 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.

Idioma: Inglés

DOI: 10.1038/s41467-020-16395-2

Año: 2020

Publicado en: NATURE COMMUNICATIONS 11, 1 (2020), 2682 [17 pp]
ISSN: 2041-1723

Factor impacto JCR: 14.919 (2020)

Categ. JCR: MULTIDISCIPLINARY SCIENCES rank: 4 / 73 = 0.055 (2020) - Q1 - T1

Factor impacto SCIMAGO: 5.559 - Biochemistry, Genetics and Molecular Biology (miscellaneous) (Q1) - Physics and Astronomy (miscellaneous) (Q1) - Chemistry (miscellaneous) (Q1)

Financiación: info:eu-repo/grantAgreement/ES/FEDER/Una manera de hacer Europa
Financiación: info:eu-repo/grantAgreement/ES/ISCIII/FIS/PI15-01507
Financiación: info:eu-repo/grantAgreement/ES/ISCIII/FIS/PI15-01715
Financiación: info:eu-repo/grantAgreement/ES/ISCIII/FIS/PI15/02101
Financiación: info:eu-repo/grantAgreement/ES/ISCIII/FIS/PI17-00082
Financiación: info:eu-repo/grantAgreement/ES/ISCIII/FIS/PI18-00267
Financiación: info:eu-repo/grantAgreement/ES/ISCIII/FIS/PI18-00757
Financiación: info:eu-repo/grantAgreement/ES/MS-ISCIII-FSE/CP16-00121

Tipo y forma: Artículo (Versión definitiva)