Por favor, use este identificador para citar o enlazar este ítem:
https://doi.org/10.1038/s41467-022-30641-9
Twittear
Título: | Persister state-directed transitioning and vulnerability in melanoma |
Fecha de publicación: | 1-jun-2022 |
Editorial: | Springer Nature |
Cita bibliográfica: | Nature Communications, volumen: 13 , nº 3055, año: 2022 |
ISSN: | 2041-1723 |
Materias relacionadas: | CDU::5 - Ciencias puras y naturales::57 - Biología::577 - Bioquímica. Biología molecular. Biofísica |
Palabras clave: | KDM5B Melanoma Heterogeneity Tumor plasticity |
Resumen: | Melanoma 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 elimination |
Autor/es principal/es: | Chauvistré, Heike Shannan, Batool Daignault-Mill, Sheena M. Ju, Robert J. Picard, Daniel Egetemaier, Stefanie Váraljai, Renáta Gibhardt, Christine Sechi, Antonio Kaschani, Farnusch Keminer, Oliver Stehbens, Samantha J. Liu, Qin Yin, Xiangfan Jeyakumar, Kirujan Vogel, Felix C.E. Krepler, Clemens Rebecca, Vito W. Kubat, Linda Lueong, Smiths S. Forster, Jan Horn, Susanne Remke, Marc Ehrmann, Michael Paschen, Annette Becker, Jürgen C. Helfrich, Iris Rauh, Daniel Kaiser, Markus Gul, Sheraz Herlyn, Meenhard Bogeski, Ivan Rodríguez López, José Neptuno Haass, Nikolas Schadendorf, Dirk Roesch, Alexander |
Facultad/Departamentos/Servicios: | Facultades, Departamentos, Servicios y Escuelas::Departamentos de la UMU::Bioquímica y Biología Molecular A |
URI: | http://hdl.handle.net/10201/138433 |
DOI: | https://doi.org/10.1038/s41467-022-30641-9 https://doi.org/10.1038/s41467-022-30641-9 |
Tipo de documento: | info:eu-repo/semantics/article |
Número páginas / Extensión: | 17 |
Derechos: | info:eu-repo/semantics/openAccess Attribution-NonCommercial-NoDerivatives 4.0 Internacional |
Descripción: | ©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/s41467-022-30641-9 Item en revisión. Pendiente de cumplimentar metadatos. |
Aparece en las colecciones: | Artículos: Bioquímica y Biología Molecular "A" |
Ficheros en este ítem:
Fichero | Descripción | Tamaño | Formato | |
---|---|---|---|---|
Nat Comm 2022.pdf | 3,38 MB | Adobe PDF | Visualizar/Abrir |
Este ítem está sujeto a una licencia Creative Commons Licencia Creative Commons