The regulators of peroxisomal acyl-carnitine shuttle CROT and CRAT promote metastasis in melanoma

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dc.contributor.authorLasheras Otero, Irene
dc.contributor.authorFeliu, Iker
dc.contributor.authorMaíllo Ruiz de Infante, Alberto
dc.contributor.authorMoreno, Haritz
dc.contributor.authorRedondo Muñoz, Marta
dc.contributor.authorAldaz Donamaría, Paula
dc.contributor.authorBocanegra Gondán, Ana Isabel
dc.contributor.authorOlías Arjona, Ana
dc.contributor.authorLecanda, Fernando
dc.contributor.authorFernández Irigoyen, Joaquín
dc.contributor.authorSantamaría Martínez, Enrique
dc.contributor.authorLarráyoz, Ignacio M.
dc.contributor.authorGómez-Cabrero, David
dc.contributor.authorWellbrock, Claudia
dc.contributor.authorVicent, Silvestre
dc.contributor.authorArozarena Martinicorena, Imanol
dc.contributor.departmentCienciases_ES
dc.contributor.departmentZientziakeu
dc.contributor.departmentCiencias de la Saludes_ES
dc.contributor.departmentOsasun Zientziakeu
dc.date.accessioned2023-05-03T08:04:20Z
dc.date.available2023-05-03T08:04:20Z
dc.date.issued2023
dc.date.updated2023-05-03T07:25:42Z
dc.description.abstractCirculating tumor cells are the key link between a primary tumor and distant metastases, but once in the bloodstream, loss of adhesion induces cell death. To identify the mechanisms relevant for melanoma circulating tumor cell survival, we performed RNA sequencing and discovered that detached melanoma cells and isolated melanoma circulating tumor cells rewire lipid metabolism by upregulating fatty acid (FA) transport and FA betaoxidation‒related genes. In patients with melanoma, high expression of FA transporters and FA beta-oxidation enzymes significantly correlates with reduced progression-free and overall survival. Among the highest expressed regulators in melanoma circulating tumor cells were the carnitine transferases carnitine O-octanoyltransferase and carnitine acetyltransferase, which control the shuttle of peroxisome-derived medium-chain FAs toward mitochondria to fuel mitochondrial FA beta-oxidation. Knockdown of carnitine O-octanoyltransferase or carnitine acetyltransferase and short-term treatment with peroxisomal or mitochondrial FA beta-oxidation inhibitors thioridazine or ranolazine suppressed melanoma metastasis in mice. Carnitine O-octanoyltransferase and carnitine acetyltransferase depletion could be rescued by medium-chain FA supplementation, indicating that the peroxisomal supply of FAs is crucial for the survival of nonadherent melanoma cells. Our study identifies targeting the FA-based cross-talk between peroxisomes and mitochondria as a potential therapeutic opportunity to challenge melanoma progression. Moreover, the discovery of the antimetastatic activity of the Food and Drug Administration‒approved drug ranolazine carries translational potential.en
dc.description.sponsorshipThis work was funded by the Instituto de Salud Carlos III-FEDER through PI16-01911 and PI19/00645 to IA. IA and IML acknowledge support through Miguel Servet II fellowships (CPII20/00011 and CPII20/00029). The Health Department of the Government of Navarra, Spain funded work through reference GºNa 71/17. SV is funded by FEDER/Ministerio de Ciencia, Innovación y Universidades - Agencia Estatal de Investigación (PID2020-116344-RB-100) and by Foundation Spanish Association Against Cancer (PROYE20029VICE). ILO is funded through a Navarrabiomed PhD studentship and the Grupo Español Multidisciplinar de Melanoma (reference Beca_GEM). FL was funded by the Cancer Research Thematic Network of the Instituto de Salud Carlos III (RTICC RD12/0036/0066, SAF2015-71606R, RTI2018-094507-B-100) financed by MCIN/AEI/10.13039/501100011033 and by FEDER. FL was also funded by the la Caixa Foundation, Caja Navarra Foundation, and the Foundation AECC. PA is a recipient of a Sara Borrell postdoctoral fellowship from the Instituto de Salud Carlos III (CD21/00137).en
dc.format.mimetypeapplication/pdfen
dc.identifier.citationLasheras-Otero, I., Feliu, I., Maillo, A., Moreno, H., Redondo-Muñoz, M., Aldaz, P., Bocanegra, A., Olias-Arjona, A., Lecanda, F., Fernandez-Irigoyen, J., Santamaria, E., Larrayoz, I. M., Gomez-Cabrero, D., Wellbrock, C., Vicent, S., & Arozarena, I. (2023). The regulators of peroxisomal acyl-carnitine shuttle crot and crat promote metastasis in melanoma. Journal of Investigative Dermatology, 143(2), 305-316.e5. https://doi.org/10.1016/j.jid.2022.08.038en
dc.identifier.doi10.1016/j.jid.2022.08.038
dc.identifier.issn0022-202X
dc.identifier.urihttps://academica-e.unavarra.es/handle/2454/45211
dc.language.isoengen
dc.publisherElsevieren
dc.relation.ispartofJournal of Investigative Dermatology, (2023) 143(2), 305-316en
dc.relation.projectIDinfo:eu-repo/grantAgreement/MINECO//PI16-01911/ES/
dc.relation.projectIDinfo:eu-repo/grantAgreement/ISCIII/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PI19%2F00645/ES/
dc.relation.projectIDinfo:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2020-116344RB-I00/ES/
dc.relation.projectIDinfo:eu-repo/grantAgreement/MINECO//AF2015-71606R/ES/
dc.relation.projectIDinfo:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/RTI2018-094507-B-I00/ES/
dc.relation.projectIDinfo:eu-repo/grantAgreement/Gobierno de Navarra//71%2F17/
dc.relation.publisherversionhttps://doi.org/10.1016/j.jid.2022.08.038
dc.rights© 2022 The Authors. This is an open access article under the CC BY-NC-ND licenseen
dc.rights.accessRightsinfo:eu-repo/semantics/openAccess
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subjectCirculating tumor cellsen
dc.subjectCell deathen
dc.subjectMelanoma metastasisen
dc.subjectLipid metabolismen
dc.subjectFA transportersen
dc.subjectCarnitine transferasesen
dc.subjectThioridazineen
dc.subjectRanolazineen
dc.subjectAntimetastatic activityen
dc.titleThe regulators of peroxisomal acyl-carnitine shuttle CROT and CRAT promote metastasis in melanomaen
dc.typeinfo:eu-repo/semantics/article
dc.type.versioninfo:eu-repo/semantics/publishedVersion
dspace.entity.typePublication
relation.isAuthorOfPublication77c888ac-462b-41e5-ba32-7f4272102203
relation.isAuthorOfPublication86d1b76e-4790-40b1-a3ec-72331c5c6199
relation.isAuthorOfPublicationabacfd17-2b93-4d99-bae2-52053d57401e
relation.isAuthorOfPublicationc447bde5-7baf-4708-b62a-2b8a15356673
relation.isAuthorOfPublication.latestForDiscovery77c888ac-462b-41e5-ba32-7f4272102203

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