000089731 001__ 89731
000089731 005__ 20220426091136.0
000089731 0247_ $$2doi$$a10.1038/s41467-020-16395-2
000089731 0248_ $$2sideral$$a118101
000089731 037__ $$aART-2020-118101
000089731 041__ $$aeng
000089731 100__ $$aAlcalá, S.
000089731 245__ $$aISG15 and ISGylation is required for pancreatic cancer stem cell mitophagy and metabolic plasticity
000089731 260__ $$c2020
000089731 5060_ $$aAccess copy available to the general public$$fUnrestricted
000089731 5203_ $$aPancreatic 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.
000089731 536__ $$9info:eu-repo/grantAgreement/ES/FEDER/Una manera de hacer Europa$$9info:eu-repo/grantAgreement/ES/ISCIII/FIS/PI15-01507$$9info:eu-repo/grantAgreement/ES/ISCIII/FIS/PI15-01715$$9info:eu-repo/grantAgreement/ES/ISCIII/FIS/PI15/02101$$9info:eu-repo/grantAgreement/ES/ISCIII/FIS/PI17-00082$$9info:eu-repo/grantAgreement/ES/ISCIII/FIS/PI18-00267$$9info:eu-repo/grantAgreement/ES/ISCIII/FIS/PI18-00757$$9info:eu-repo/grantAgreement/ES/MS-ISCIII-FSE/CP16-00121
000089731 540__ $$9info:eu-repo/semantics/openAccess$$aby$$uhttp://creativecommons.org/licenses/by/3.0/es/
000089731 590__ $$a14.919$$b2020
000089731 591__ $$aMULTIDISCIPLINARY SCIENCES$$b4 / 73 = 0.055$$c2020$$dQ1$$eT1
000089731 592__ $$a5.559$$b2020
000089731 593__ $$aBiochemistry, Genetics and Molecular Biology (miscellaneous)$$c2020$$dQ1
000089731 593__ $$aPhysics and Astronomy (miscellaneous)$$c2020$$dQ1
000089731 593__ $$aChemistry (miscellaneous)$$c2020$$dQ1
000089731 655_4 $$ainfo:eu-repo/semantics/article$$vinfo:eu-repo/semantics/publishedVersion
000089731 700__ $$0(orcid)0000-0002-8624-8757$$aSancho, P.
000089731 700__ $$aMartinelli, P.
000089731 700__ $$aNavarro, D.
000089731 700__ $$aPedrero, C.
000089731 700__ $$aMartín-Hijano, L.
000089731 700__ $$aValle, S.
000089731 700__ $$aEarl, J.
000089731 700__ $$aRodríguez-Serrano, M.
000089731 700__ $$aRuiz-Cañas, L.
000089731 700__ $$aRojas, K.
000089731 700__ $$aCarrato, A.
000089731 700__ $$aGarcía-Bermejo, L.
000089731 700__ $$aFernández-Moreno, M.Á.
000089731 700__ $$aHermann, P.C.
000089731 700__ $$aSainz, B.
000089731 700__ $$a, Jr.
000089731 773__ $$g11, 1 (2020), 2682 [17 pp]$$pNATURE COMMUNICATIONS$$tNATURE COMMUNICATIONS$$x2041-1723
000089731 8564_ $$s1823566$$uhttps://zaguan.unizar.es/record/89731/files/texto_completo.pdf$$yVersión publicada
000089731 8564_ $$s60062$$uhttps://zaguan.unizar.es/record/89731/files/texto_completo.jpg?subformat=icon$$xicon$$yVersión publicada
000089731 909CO $$ooai:zaguan.unizar.es:89731$$particulos$$pdriver
000089731 951__ $$a2022-04-26-08:53:48
000089731 980__ $$aARTICLE