Oncogenic enhancers prime quiescent metastatic cells to escape NK immune surveillance by eliciting transcriptional memory

Metastasis arises from disseminated tumour cells (DTCs) that are characterized by intrinsic phenotypic plasticity and the capability of seeding to secondary organs. DTCs can remain latent for years before giving rise to symptomatic overt metastasis. In this context, DTCs fluctuate between a quiescen...

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Autores: Michelatti, Daniela, Beyes, Sven, Bernardis, Chiara, Negri, Maria Luce, Morelli, Leonardo, García Bediaga, Naiara, Poli, Vittoria, Fagnocchi, Luca, Lago, Sara, D’Annunzio, Sarah, Cona, Nicole, Gaspardo, Ilaria, Bianchi, Aurora, Jovetic, Jovana, Gianesello, Matteo, Turdo, Alice, D’Accardo, Caterina, Gaggianesi, Miriam, Dori, Martina, Forcato, Mattia, Crispatzu, Giuliano, Rada-Iglesias, Álvaro, Sosa, María Soledad, Timmers, H. T. Marc, Bicciato, Silvio, Todaro, Matilde, Tiberi, Luca, Zippo, Alessio
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2024
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/364561
Acceso en línea:http://hdl.handle.net/10261/364561
Access Level:acceso abierto
Palabra clave:Cell-cycle exit
Chromatin
Metastasis
Transcriptional regulatory elements
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spelling Oncogenic enhancers prime quiescent metastatic cells to escape NK immune surveillance by eliciting transcriptional memoryMichelatti, DanielaBeyes, SvenBernardis, ChiaraNegri, Maria LuceMorelli, LeonardoGarcía Bediaga, NaiaraPoli, VittoriaFagnocchi, LucaLago, SaraD’Annunzio, SarahCona, NicoleGaspardo, IlariaBianchi, AuroraJovetic, JovanaGianesello, MatteoTurdo, AliceD’Accardo, CaterinaGaggianesi, MiriamDori, MartinaForcato, MattiaCrispatzu, GiulianoRada-Iglesias, ÁlvaroSosa, María SoledadTimmers, H. T. MarcBicciato, SilvioTodaro, MatildeTiberi, LucaZippo, AlessioCell-cycle exitChromatinMetastasisTranscriptional regulatory elementsMetastasis arises from disseminated tumour cells (DTCs) that are characterized by intrinsic phenotypic plasticity and the capability of seeding to secondary organs. DTCs can remain latent for years before giving rise to symptomatic overt metastasis. In this context, DTCs fluctuate between a quiescent and proliferative state in response to systemic and microenvironmental signals including immune-mediated surveillance. Despite its relevance, how intrinsic mechanisms sustain DTCs plasticity has not been addressed. By interrogating the epigenetic state of metastatic cells, we find that tumour progression is coupled with the activation of oncogenic enhancers that are organized in variable interconnected chromatin domains. This spatial chromatin context leads to the activation of a robust transcriptional response upon repeated exposure to retinoic acid (RA). We show that this adaptive mechanism sustains the quiescence of DTCs through the activation of the master regulator SOX9. Finally, we determine that RA-stimulated transcriptional memory increases the fitness of metastatic cells by supporting the escape of quiescent DTCs from NK-mediated immune surveillance. Overall, these findings highlight the contribution of oncogenic enhancers in establishing transcriptional memories as an adaptive mechanism to reinforce cancer dormancy and immune escape, thus amenable for therapeutic intervention.Work in the Zippo group was supported by grants from the AIRC foundation (IG 2019-22911) and European Union under the Horizon 2020 Framework Programme H2020 Future and Emerging Technologies (801336; - PROCHIP). Work in the Todaro group was supported by grants from the AIRC foundation (IG 2018—ID. 21492). S. Beyes was supported by the Deutsche Forschungsgemeinschaft (DFG—BE 7359/1-1). V. Poli and S. Lago were recipients of AIRC fellowships (21158 and 25373).Peer reviewedSpringer NatureAssociazione Italiana per la Ricerca sul CancroEuropean CommissionGerman Research FoundationConsejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]202420242024info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionapplication/pdfhttp://hdl.handle.net/10261/364561reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/EC/H2020/801336The underlying dataset has been published as supplementary material of the article in the publisher platform at DOI https://doi.org/10.1038/s41467-024-46524-0https://doi.org/10.1038/s41467-024-46524-0Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/3645612026-05-22T06:33:51Z
dc.title.none.fl_str_mv Oncogenic enhancers prime quiescent metastatic cells to escape NK immune surveillance by eliciting transcriptional memory
title Oncogenic enhancers prime quiescent metastatic cells to escape NK immune surveillance by eliciting transcriptional memory
spellingShingle Oncogenic enhancers prime quiescent metastatic cells to escape NK immune surveillance by eliciting transcriptional memory
Michelatti, Daniela
Cell-cycle exit
Chromatin
Metastasis
Transcriptional regulatory elements
title_short Oncogenic enhancers prime quiescent metastatic cells to escape NK immune surveillance by eliciting transcriptional memory
title_full Oncogenic enhancers prime quiescent metastatic cells to escape NK immune surveillance by eliciting transcriptional memory
title_fullStr Oncogenic enhancers prime quiescent metastatic cells to escape NK immune surveillance by eliciting transcriptional memory
title_full_unstemmed Oncogenic enhancers prime quiescent metastatic cells to escape NK immune surveillance by eliciting transcriptional memory
title_sort Oncogenic enhancers prime quiescent metastatic cells to escape NK immune surveillance by eliciting transcriptional memory
dc.creator.none.fl_str_mv Michelatti, Daniela
Beyes, Sven
Bernardis, Chiara
Negri, Maria Luce
Morelli, Leonardo
García Bediaga, Naiara
Poli, Vittoria
Fagnocchi, Luca
Lago, Sara
D’Annunzio, Sarah
Cona, Nicole
Gaspardo, Ilaria
Bianchi, Aurora
Jovetic, Jovana
Gianesello, Matteo
Turdo, Alice
D’Accardo, Caterina
Gaggianesi, Miriam
Dori, Martina
Forcato, Mattia
Crispatzu, Giuliano
Rada-Iglesias, Álvaro
Sosa, María Soledad
Timmers, H. T. Marc
Bicciato, Silvio
Todaro, Matilde
Tiberi, Luca
Zippo, Alessio
author Michelatti, Daniela
author_facet Michelatti, Daniela
Beyes, Sven
Bernardis, Chiara
Negri, Maria Luce
Morelli, Leonardo
García Bediaga, Naiara
Poli, Vittoria
Fagnocchi, Luca
Lago, Sara
D’Annunzio, Sarah
Cona, Nicole
Gaspardo, Ilaria
Bianchi, Aurora
Jovetic, Jovana
Gianesello, Matteo
Turdo, Alice
D’Accardo, Caterina
Gaggianesi, Miriam
Dori, Martina
Forcato, Mattia
Crispatzu, Giuliano
Rada-Iglesias, Álvaro
Sosa, María Soledad
Timmers, H. T. Marc
Bicciato, Silvio
Todaro, Matilde
Tiberi, Luca
Zippo, Alessio
author_role author
author2 Beyes, Sven
Bernardis, Chiara
Negri, Maria Luce
Morelli, Leonardo
García Bediaga, Naiara
Poli, Vittoria
Fagnocchi, Luca
Lago, Sara
D’Annunzio, Sarah
Cona, Nicole
Gaspardo, Ilaria
Bianchi, Aurora
Jovetic, Jovana
Gianesello, Matteo
Turdo, Alice
D’Accardo, Caterina
Gaggianesi, Miriam
Dori, Martina
Forcato, Mattia
Crispatzu, Giuliano
Rada-Iglesias, Álvaro
Sosa, María Soledad
Timmers, H. T. Marc
Bicciato, Silvio
Todaro, Matilde
Tiberi, Luca
Zippo, Alessio
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Associazione Italiana per la Ricerca sul Cancro
European Commission
German Research Foundation
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv Cell-cycle exit
Chromatin
Metastasis
Transcriptional regulatory elements
topic Cell-cycle exit
Chromatin
Metastasis
Transcriptional regulatory elements
description Metastasis arises from disseminated tumour cells (DTCs) that are characterized by intrinsic phenotypic plasticity and the capability of seeding to secondary organs. DTCs can remain latent for years before giving rise to symptomatic overt metastasis. In this context, DTCs fluctuate between a quiescent and proliferative state in response to systemic and microenvironmental signals including immune-mediated surveillance. Despite its relevance, how intrinsic mechanisms sustain DTCs plasticity has not been addressed. By interrogating the epigenetic state of metastatic cells, we find that tumour progression is coupled with the activation of oncogenic enhancers that are organized in variable interconnected chromatin domains. This spatial chromatin context leads to the activation of a robust transcriptional response upon repeated exposure to retinoic acid (RA). We show that this adaptive mechanism sustains the quiescence of DTCs through the activation of the master regulator SOX9. Finally, we determine that RA-stimulated transcriptional memory increases the fitness of metastatic cells by supporting the escape of quiescent DTCs from NK-mediated immune surveillance. Overall, these findings highlight the contribution of oncogenic enhancers in establishing transcriptional memories as an adaptive mechanism to reinforce cancer dormancy and immune escape, thus amenable for therapeutic intervention.
publishDate 2024
dc.date.none.fl_str_mv 2024
2024
2024
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Publisher's version
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/364561
url http://hdl.handle.net/10261/364561
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv #PLACEHOLDER_PARENT_METADATA_VALUE#
info:eu-repo/grantAgreement/EC/H2020/801336
The underlying dataset has been published as supplementary material of the article in the publisher platform at DOI https://doi.org/10.1038/s41467-024-46524-0
https://doi.org/10.1038/s41467-024-46524-0
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Springer Nature
publisher.none.fl_str_mv Springer Nature
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
repository.name.fl_str_mv
repository.mail.fl_str_mv
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