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

Daniela Michelatti, Sven Beyes, Chiara Bernardis, Maria Luce Negri, Leonardo Morelli, Naiara Garcia Bediaga, Vittoria Poli, Luca Fagnocchi, Sara Lago, Sarah D’Annunzio, Nicole Cona, Ilaria Gaspardo, Aurora Bianchi, Jovana Jovetic, Matteo Gianesello, Alice Turdo, Caterina D’Accardo, Miriam Gaggianesi, Martina Dori, Mattia ForcatoGiuliano Crispatzu, Alvaro Rada-Iglesias, Maria Soledad Sosa, H. T.Marc Timmers, Silvio Bicciato, Matilde Todaro, Luca Tiberi, Alessio Zippo

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Article number2198
JournalNature Communications
Volume15
Issue number1
DOIs
StatePublished - Dec 2024

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