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

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...

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Detalles Bibliográficos
Autores: 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, Bruno
Tipo de recurso: artículo
Fecha de publicación:2020
País:España
Institución:Universidad Autónoma de Madrid
Repositorio:Biblos-e Archivo. Repositorio Institucional de la UAM
Idioma:inglés
OAI Identifier:oai:repositorio.uam.es:10486/693542
Acceso en línea:http://hdl.handle.net/10486/693542
https://dx.doi.org/10.1038/s41467-020-16395-2
Access Level:acceso abierto
Palabra clave:Cancer
Cell
Metabolism
Mitochondrial DNA
Plasticity
Tumor
Biología y Biomedicina / Biología
Descripción
Sumario: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

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