Oncogenic enhancers prime quiescent metastatic cells to escape NK immune surveillance by eliciting transcriptional memory
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Published:2024-03-19
Issue:1
Volume:15
Page:
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ISSN:2041-1723
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Container-title:Nature Communications
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language:en
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Short-container-title:Nat Commun
Author:
Michelatti Daniela, Beyes Sven, Bernardis Chiara, Negri Maria Luce, Morelli LeonardoORCID, Bediaga Naiara Garcia, Poli Vittoria, Fagnocchi LucaORCID, Lago SaraORCID, D’Annunzio Sarah, Cona Nicole, Gaspardo Ilaria, Bianchi Aurora, Jovetic Jovana, Gianesello Matteo, Turdo AliceORCID, D’Accardo Caterina, Gaggianesi Miriam, Dori Martina, Forcato MattiaORCID, Crispatzu GiulianoORCID, Rada-Iglesias AlvaroORCID, Sosa Maria Soledad, Timmers H. T. MarcORCID, Bicciato SilvioORCID, Todaro MatildeORCID, Tiberi LucaORCID, Zippo AlessioORCID
Abstract
AbstractMetastasis 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.
Funder
Associazione Italiana per la Ricerca sul Cancro EC | Horizon 2020 Framework Programme
Publisher
Springer Science and Business Media LLC
Reference81 articles.
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