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

Sonia Alcalá (), Patricia Sancho, Paola Martinelli, Diego Navarro, Coral Pedrero, Laura Martín-Hijano, Sandra Valle, Julie Earl, Macarena Rodríguez-Serrano, Laura Ruiz-Cañas, Katerin Rojas, Alfredo Carrato, Laura García-Bermejo, Miguel Ángel Fernández-Moreno, Patrick C. Hermann and Bruno Sainz ()
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Sonia Alcalá: Universidad Autónoma de Madrid (UAM) and Instituto de Investigaciones Biomédicas “Alberto Sols” (IIBM), CSIC-UAM
Patricia Sancho: IIS Aragón, Hospital Universitario Miguel Servet
Paola Martinelli: Medical University Vienna
Diego Navarro: Universidad Autónoma de Madrid (UAM) and Instituto de Investigaciones Biomédicas “Alberto Sols” (IIBM), CSIC-UAM
Coral Pedrero: Universidad Autónoma de Madrid (UAM) and Instituto de Investigaciones Biomédicas “Alberto Sols” (IIBM), CSIC-UAM
Laura Martín-Hijano: Universidad Autónoma de Madrid (UAM) and Instituto de Investigaciones Biomédicas “Alberto Sols” (IIBM), CSIC-UAM
Sandra Valle: Universidad Autónoma de Madrid (UAM) and Instituto de Investigaciones Biomédicas “Alberto Sols” (IIBM), CSIC-UAM
Julie Earl: Chronic Diseases and Cancer Area 3—Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS)
Macarena Rodríguez-Serrano: Biomarkers and Therapeutic Targets Group—IRYCIS
Laura Ruiz-Cañas: Universidad Autónoma de Madrid (UAM) and Instituto de Investigaciones Biomédicas “Alberto Sols” (IIBM), CSIC-UAM
Katerin Rojas: Universidad Autónoma de Madrid (UAM) and Instituto de Investigaciones Biomédicas “Alberto Sols” (IIBM), CSIC-UAM
Alfredo Carrato: Chronic Diseases and Cancer Area 3—Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS)
Laura García-Bermejo: Biomarkers and Therapeutic Targets Group—IRYCIS
Miguel Ángel Fernández-Moreno: Universidad Autónoma de Madrid (UAM) and Instituto de Investigaciones Biomédicas “Alberto Sols” (IIBM), CSIC-UAM
Patrick C. Hermann: Ulm University
Bruno Sainz: Universidad Autónoma de Madrid (UAM) and Instituto de Investigaciones Biomédicas “Alberto Sols” (IIBM), CSIC-UAM

Nature Communications, 2020, vol. 11, issue 1, 1-17

Abstract: 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 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.

Date: 2020
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DOI: 10.1038/s41467-020-16395-2

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