ISG15 and ISGylation is required for pancreatic cancer stem cell mitophagy and metabolic plasticity
Author
Alcalá, Sonia; Sancho, Patricia; Martinelli, Paola; Navarro, Diego; Pedrero, Coral; Martín-Hijano, Laura; Valle, Sandra; Earl, Julie; Rodríguez-Serrano, Macarena; Ruiz-Cañas, Laura; Rojas, Katerin; Carrato, Alfredo; García-Bermejo, Laura; Fernández-Moreno, Miguel Ángel; Hermann, Patrick C.; Sainz, BrunoEntity
UAM. Departamento de BioquímicaPublisher
Nature Publishing GroupDate
2020-12-01Citation
10.1038/s41467-020-16395-2
Nature Communications 11.1 (2020): 2682
ISSN
2041-1723DOI
10.1038/s41467-020-16395-2Funded by
We want to particularly acknowledge the patients and the BioBank Hospital Ramón y Cajal-IRYCIS (PT13/0010/0002) integrated in the Spanish National Biobanks Network for its collaboration. This study was supported by a Ramón y Cajal Merit Award (RYC-2012-12104) from the Ministerio de Economía y Competitividad, Spain (B.S.); a Conquer Cancer Now Grant from the Concern Foundation (Los Angeles, CA, USA) (B.S.); a Coordinated grant from the Fundación Asociación Española Contra el Cáncer (AECC, GC16173694BARB) (A.C. and B.S.); funding from The Fero Foundation (B.S.); Fondo de Investigaciones Sanitarias (FIS) grants PI15/01507 and PI18/00757 (B.S.), PI15/01715 and PI18/00267 (M.L.G-B.), PI17/00082 (P.S.) and PI15/02101 (A.C.) (all co-financed through Fondo Europeo de Desarrollo Regional (FEDER) “Una manera de hacer Europa”) and a Miguel Servet award (CP16/00121) (P.S.), all from the Instituto de Salud Carlos III (ISCIII), Spain; funding from the Biomedical Research Network in Cancer (CIBERONC:CB16/12/00446) for clinical sample and data collection (A.C.); a Max Eder Fellowship of the German Cancer Aid (111746) (P.C.H.); the German Research Foundation (DFG, CRC 1279 “Exploiting the human peptidome for Novel Antimicrobial and Anticancer Agents”) (P.C.H.); and the Austrian Science Fund (FWF-B27361) and Ingrid Shaker-Nessmann Foundation for Cancer Research (P.M.).Editor's Version
https://dx.doi.org/10.1038/s41467-020-16395-2Subjects
Cancer; Cell; Metabolism; Mitochondrial DNA; Plasticity; Tumor; Biología y Biomedicina / BiologíaRights
© 2020, The Author(s)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 interferonstimulated 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
Files in this item
Google Scholar:Alcalá, Sonia
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Sancho, Patricia
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Martinelli, Paola
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Navarro, Diego
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Pedrero, Coral
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Martín-Hijano, Laura
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Valle, Sandra
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Earl, Julie
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Rodríguez-Serrano, Macarena
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Ruiz-Cañas, Laura
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Rojas, Katerin
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Carrato, Alfredo
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García-Bermejo, Laura
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Fernández-Moreno, Miguel Ángel
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Hermann, Patrick C.
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Sainz, Bruno
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