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Persister state-directed transitioning and vulnerability in melanoma

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dc.contributor.authorChauvistré, Heike
dc.contributor.authorShannan, Batool
dc.contributor.authorDaignault-Mill, Sheena M.
dc.contributor.authorJu, Robert J.
dc.contributor.authorPicard, Daniel
dc.contributor.authorEgetemaier, Stefanie
dc.contributor.authorVáraljai, Renáta
dc.contributor.authorGibhardt, Christine
dc.contributor.authorSechi, Antonio
dc.contributor.authorKaschani, Farnusch
dc.contributor.authorKeminer, Oliver
dc.contributor.authorStehbens, Samantha J.
dc.contributor.authorLiu, Qin
dc.contributor.authorYin, Xiangfan
dc.contributor.authorJeyakumar, Kirujan
dc.contributor.authorVogel, Felix C.E.
dc.contributor.authorKrepler, Clemens
dc.contributor.authorRebecca, Vito W.
dc.contributor.authorKubat, Linda
dc.contributor.authorLueong, Smiths S.
dc.contributor.authorForster, Jan
dc.contributor.authorHorn, Susanne
dc.contributor.authorRemke, Marc
dc.contributor.authorEhrmann, Michael
dc.contributor.authorPaschen, Annette
dc.contributor.authorBecker, Jürgen C.
dc.contributor.authorHelfrich, Iris
dc.contributor.authorRauh, Daniel
dc.contributor.authorKaiser, Markus
dc.contributor.authorGul, Sheraz
dc.contributor.authorHerlyn, Meenhard
dc.contributor.authorBogeski, Ivan
dc.contributor.authorHaass, Nikolas
dc.contributor.authorSchadendorf, Dirk
dc.contributor.authorRoesch, Alexander
dc.contributor.authorRodríguez López, José Neptuno
dc.contributor.departmentBioquímica y Biología Molecular Aes
dc.date.accessioned2024-02-01T13:03:36Z
dc.date.available2024-02-01T13:03:36Z
dc.date.issued2022-06-01
dc.description©2022. This manuscript version is made available under the CC-BY 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/ This document is the Published Manuscript version of a Published Work that appeared in final form in Nature Communications. To access the final edited and published work see https://doi.org/10.1038/s41467-022-30641-9es
dc.descriptionItem en revisión. Pendiente de cumplimentar metadatos.
dc.description.abstractMelanoma is a highly plastic tumor characterized by dynamic interconversion of different cell identities depending on the biological context. Melanoma cells with high expression of the H3K4 demethylase KDM5B (JARID1B) rest in a slow-cycling, yet reversible persister state. Over time, KDM5Bhigh cells can promote rapid tumor repopulation with equilibrated KDM5B expression heterogeneity. The cellular identity of KDM5Bhigh persister cells has not been studied so far, missing an important cell state-directed treatment opportunity in melanoma. Here, we have established a doxycycline-titratable system for genetic induction of permanent intratumor expression of KDM5B and screened for chemical agents that phenocopy this effect. Transcriptional profiling and cell functional assays confirmed that the dihydropyridine 2-phenoxyethyl 4-(2-fluorophenyl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexa-hydro-quinoline-3-carboxylate (termed Cpd1) supports high KDM5B expression and directs melanoma cells towards differentiation along the melanocytic lineage and to cell cycle-arrest. The high KDM5B state additionally prevents cell proliferation through negative regulation of cytokinetic abscission. Moreover, treatment with Cpd1 promoted the expression of the melanocyte-specific tyrosinase gene specifically sensitizing melanoma cells for the tyrosinase-processed antifolate prodrug 3-O-(3,4,5-trimethoxybenzoyl)-(-)-epicatechin (TMECG). In summary, our study provides proof-of-concept for a dual hit strategy in melanoma, in which persister state-directed transitioning limits tumor plasticity and primes melanoma cells towards lineage-specific eliminationes
dc.formatapplication/pdfes
dc.format.extent17es
dc.identifier.citationNature Communications, volumen: 13 , nº 3055, año: 2022
dc.identifier.doihttps://doi.org/10.1038/s41467-022-30641-9
dc.identifier.doihttps://doi.org/10.1038/s41467-022-30641-9
dc.identifier.issn2041-1723
dc.identifier.urihttp://hdl.handle.net/10201/138433
dc.languageenges
dc.publisherSpringer Naturees
dc.relation- Ámbito del proyecto: Nacional o regional - Agencia financiadora: Ministerio de Economia y Competitividad (MINECO; Co-financing with Fondos FEDER) y Fundación Séneca, the Región de Murcia (FS-RM) - Código o número del acuerdo de subvención: SAF2016-77241-R y 20809/PI/18es
dc.relation.isreplacedby10.1038/s41467-022-30641-9es
dc.rightsinfo:eu-repo/semantics/openAccesses
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 Internacional*
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/*
dc.subjectKDM5Bes
dc.subjectMelanomaes
dc.subjectHeterogeneityes
dc.subjectTumor plasticityes
dc.subject.otherCDU::5 - Ciencias puras y naturales::57 - Biología::577 - Bioquímica. Biología molecular. Biofísicaes
dc.titlePersister state-directed transitioning and vulnerability in melanomaes
dc.typeinfo:eu-repo/semantics/articlees
dspace.entity.typePublicationes
relation.isAuthorOfPublication36d7ac7e-b9a7-477c-8f7e-f03d4cc834c1
relation.isAuthorOfPublication.latestForDiscovery36d7ac7e-b9a7-477c-8f7e-f03d4cc834c1
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