Persister state-directed transitioning and vulnerability in melanoma

Heike Chauvistré, Batool Shannan, Sheena M. Daignault-Mill, Robert J. Ju, Daniel Picard, Stefanie Egetemaier, Renáta Váraljai, Christine S. Gibhardt, Antonio Sechi, Farnusch Kaschani, Oliver Keminer, Samantha J. Stehbens, Qin Liu, Xiangfan Yin, Kirujan Jeyakumar, Felix C. E. Vogel, Clemens Krepler, Vito W. Rebecca, Linda Kubat, Smiths S. Lueong, Jan Forster, Susanne Horn, Marc Remke, Michael Ehrmann, Annette Paschen, Jürgen C. Becker, Iris Helfrich, Daniel Rauh, Markus Kaiser, Sheraz Gul, Meenhard Herlyn, Ivan Bogeski, José Neptuno Rodríguez-López, Nikolas K. Haass, Dirk Schadendorf and Alexander Roesch ()
Additional contact information
Heike Chauvistré: University Hospital Essen, West German Cancer Center, University Duisburg-Essen
Batool Shannan: University Hospital Essen, West German Cancer Center, University Duisburg-Essen
Sheena M. Daignault-Mill: The University of Queensland Diamantina Institute, The University of Queensland
Robert J. Ju: The University of Queensland Diamantina Institute, The University of Queensland
Daniel Picard: German Consortium for Translational Cancer Research (DKTK), Partner Site Essen/Düsseldorf
Stefanie Egetemaier: University Hospital Essen, West German Cancer Center, University Duisburg-Essen
Renáta Váraljai: University Hospital Essen, West German Cancer Center, University Duisburg-Essen
Christine S. Gibhardt: University Medical Center, Georg-August-University
Antonio Sechi: RWTH Aachen University Medical School
Farnusch Kaschani: University of Duisburg-Essen
Oliver Keminer: Fraunhofer Institute for Translational Medicine and Pharmacology ITMP
Samantha J. Stehbens: The University of Queensland Diamantina Institute, The University of Queensland
Qin Liu: The Wistar Institute
Xiangfan Yin: The Wistar Institute
Kirujan Jeyakumar: TU Dortmund University
Felix C. E. Vogel: University Hospital Essen, West German Cancer Center, University Duisburg-Essen
Clemens Krepler: The Wistar Institute
Vito W. Rebecca: The Wistar Institute
Linda Kubat: German Consortium for Translational Cancer Research (DKTK), Partner Site Essen/Düsseldorf
Smiths S. Lueong: German Consortium for Translational Cancer Research (DKTK), Partner Site Essen/Düsseldorf
Jan Forster: German Consortium for Translational Cancer Research (DKTK), Partner Site Essen/Düsseldorf
Susanne Horn: University Hospital Essen, West German Cancer Center, University Duisburg-Essen
Marc Remke: German Consortium for Translational Cancer Research (DKTK), Partner Site Essen/Düsseldorf
Michael Ehrmann: University of Duisburg-Essen
Annette Paschen: University Hospital Essen, West German Cancer Center, University Duisburg-Essen
Jürgen C. Becker: University Hospital Essen, West German Cancer Center, University Duisburg-Essen
Iris Helfrich: University Hospital Essen, West German Cancer Center, University Duisburg-Essen
Daniel Rauh: TU Dortmund University
Markus Kaiser: University of Duisburg-Essen
Sheraz Gul: Fraunhofer Institute for Translational Medicine and Pharmacology ITMP
Meenhard Herlyn: The Wistar Institute
Ivan Bogeski: University Medical Center, Georg-August-University
José Neptuno Rodríguez-López: Regional Campus of International Excellence ‘Campus Mare Nostrum’, University of Murcia
Nikolas K. Haass: The University of Queensland Diamantina Institute, The University of Queensland
Dirk Schadendorf: University Hospital Essen, West German Cancer Center, University Duisburg-Essen
Alexander Roesch: University Hospital Essen, West German Cancer Center, University Duisburg-Essen

Nature Communications, 2022, vol. 13, issue 1, 1-17

Abstract: 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.

Date: 2022
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-022-30641-9 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-30641-9

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-022-30641-9

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().