The team of Professor Bruno Sainz Jr from Universidad Autónoma de Madrid recently studied the mechanism of cancer stem cells in pancreatic cancer and found that PaCSCs increase ISG15 and ISGylation expression to maintain their metabolic plasticity and the mitophagy process of mitochondria.
Congratulations to researchers for publishing the latest articles in the top-level journal "Nature Communications". It is a great honor for Elabscience's products to contribute to this great scientific research achievement. Elabscience is determined to be strict with itself and be the most loyal partner of scientific research scholars!
Title: ISG15 and ISGylation is required for pancreatic cancer stem cell mitophagy and metabolic plasticity
Journal: Nature Communications
Institution of the first author: Universidad Autónoma de Madrid, Spain.
Institution of the corresponding author: Universidad Autónoma de Madrid, Spain.
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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.
1. This research indicated that PaCSCs increase expression of ISG15 and ISGylation to maintain their metabolic plasticity and the mitophagy of mitochondria.
2. ISG15 loss results in decreased mitochondrial ISGylation concomitant with increased accumulation dysfunctional mitochondria, reduced oxidative phosphorylation (OXPHOS) and impaired mitophagy.
3. This study highlights a direct link between ISG15/ISGylation and metabolic plasticity in PaCSCs, and strongly argues for further research into the development of inhibitors of ISG15/ISGylation for pancreatic ductal adenocarcinoma (PDAC).
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