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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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
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spelling ISG15 and ISGylation is required for pancreatic cancer stem cell mitophagy and metabolic plasticityAlcalá, SoniaSancho, PatriciaMartinelli, PaolaNavarro, DiegoPedrero, CoralMartín-Hijano, LauraValle, SandraEarl, JulieRodríguez-Serrano, MacarenaRuiz-Cañas, LauraRojas, KaterinCarrato, AlfredoGarcía-Bermejo, LauraFernández Moreno, Miguel ÁngelHermann, Patrick C.Sainz, BrunoCancerCellMetabolismMitochondrial DNAPlasticityTumorBiología y Biomedicina / BiologíaPancreatic 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 stemnessWe 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.).Nature Publishing GroupDepartamento de BioquímicaFacultad de Medicina20202020-12-01research articlehttp://purl.org/coar/resource_type/c_2df8fbb1VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10486/693542https://dx.doi.org/10.1038/s41467-020-16395-2reponame:Biblos-e Archivo. Repositorio Institucional de la UAMinstname:Universidad Autónoma de MadridInglésengopen accesshttp://purl.org/coar/access_right/c_abf2info:eu-repo/semantics/openAccessoai:repositorio.uam.es:10486/6935422026-06-23T12:46:27Z
dc.title.none.fl_str_mv ISG15 and ISGylation is required for pancreatic cancer stem cell mitophagy and metabolic plasticity
title ISG15 and ISGylation is required for pancreatic cancer stem cell mitophagy and metabolic plasticity
spellingShingle ISG15 and ISGylation is required for pancreatic cancer stem cell mitophagy and metabolic plasticity
Alcalá, Sonia
Cancer
Cell
Metabolism
Mitochondrial DNA
Plasticity
Tumor
Biología y Biomedicina / Biología
title_short ISG15 and ISGylation is required for pancreatic cancer stem cell mitophagy and metabolic plasticity
title_full ISG15 and ISGylation is required for pancreatic cancer stem cell mitophagy and metabolic plasticity
title_fullStr ISG15 and ISGylation is required for pancreatic cancer stem cell mitophagy and metabolic plasticity
title_full_unstemmed ISG15 and ISGylation is required for pancreatic cancer stem cell mitophagy and metabolic plasticity
title_sort ISG15 and ISGylation is required for pancreatic cancer stem cell mitophagy and metabolic plasticity
dc.creator.none.fl_str_mv 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
author Alcalá, Sonia
author_facet 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
author_role author
author2 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
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Departamento de Bioquímica
Facultad de Medicina
dc.subject.none.fl_str_mv Cancer
Cell
Metabolism
Mitochondrial DNA
Plasticity
Tumor
Biología y Biomedicina / Biología
topic Cancer
Cell
Metabolism
Mitochondrial DNA
Plasticity
Tumor
Biología y Biomedicina / Biología
description 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
publishDate 2020
dc.date.none.fl_str_mv 2020
2020-12-01
dc.type.none.fl_str_mv research article
http://purl.org/coar/resource_type/c_2df8fbb1
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv http://hdl.handle.net/10486/693542
https://dx.doi.org/10.1038/s41467-020-16395-2
url http://hdl.handle.net/10486/693542
https://dx.doi.org/10.1038/s41467-020-16395-2
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Nature Publishing Group
publisher.none.fl_str_mv Nature Publishing Group
dc.source.none.fl_str_mv reponame:Biblos-e Archivo. Repositorio Institucional de la UAM
instname:Universidad Autónoma de Madrid
instname_str Universidad Autónoma de Madrid
reponame_str Biblos-e Archivo. Repositorio Institucional de la UAM
collection Biblos-e Archivo. Repositorio Institucional de la UAM
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15.301603

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