Publication: Persister state-directed transitioning and vulnerability in melanoma
Authors
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 ; Haass, Nikolas ; Schadendorf, Dirk ; Roesch, Alexander ; Rodríguez López, José Neptuno
item.page.secondaryauthor
item.page.director
Publisher
Springer Nature
publication.page.editor
publication.page.department
DOI
https://doi.org/10.1038/s41467-022-30641-9
https://doi.org/10.1038/s41467-022-30641-9
https://doi.org/10.1038/s41467-022-30641-9
item.page.type
info:eu-repo/semantics/article
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/s41467-022-30641-9
Item en revisión. Pendiente de cumplimentar metadatos.
Item en revisión. Pendiente de cumplimentar metadatos.
Abstract
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
publication.page.subject
Citation
Nature Communications, volumen: 13 , nº 3055, año: 2022
item.page.embargo
Collections
Ir a Estadísticas
Este ítem está sujeto a una licencia Creative Commons. http://creativecommons.org/licenses/by-nc-nd/4.0/