ISG15 and ISGylation is required for pancreatic cancer stem cell mitophagy and metabolic plasticity
Autor: | 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. |
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Přispěvatelé: | Ministerio de Economía y Competitividad (España), Concern Foundation, Fundación Científica Asociación Española Contra el Cáncer, Fundación Fero, Instituto de Salud Carlos III, European Commission, German Cancer Aid, German Research Foundation, Austrian Science Fund, UAM. Departamento de Bioquímica |
Rok vydání: | 2020 |
Předmět: |
0301 basic medicine
Cell Plasticity General Physics and Astronomy Mitochondrion medicine.disease_cause Oxidative Phosphorylation Metastasis 0302 clinical medicine Mitophagy lcsh:Science Cancer Multidisciplinary Tumor Cancer stem cells Biología y Biomedicina / Biología Cancer metabolism Metformin Mitochondrial DNA Mitochondria Cell biology Cell Transformation Neoplastic 030220 oncology & carcinogenesis Neoplastic Stem Cells Cytokines Stem cell Carcinoma Pancreatic Ductal Plasticity Science Oxidative phosphorylation Biology Article General Biochemistry Genetics and Molecular Biology Cell Line 03 medical and health sciences Pancreatic cancer medicine Humans Ubiquitins General Chemistry medicine.disease ISG15 Pancreatic Neoplasms 030104 developmental biology Metabolism lcsh:Q RNA Editing Cell Carcinogenesis |
Zdroj: | Digital.CSIC. Repositorio Institucional del CSIC instname Biblos-e Archivo: Repositorio Institucional de la UAM Universidad Autónoma de Madrid Nature Communications, Vol 11, Iss 1, Pp 1-17 (2020) Biblos-e Archivo. Repositorio Institucional de la UAM Nature Communications Zaguán. Repositorio Digital de la Universidad de Zaragoza Zaguán: Repositorio Digital de la Universidad de Zaragoza Universidad de Zaragoza |
ISSN: | 2012-1210 |
Popis: | 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. 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.). |
Databáze: | OpenAIRE |
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