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 Forcato, Giuliano Crispatzu, Alvaro Rada-Iglesias, Maria Soledad Sosa, H. T. Marc Timmers, Silvio Bicciato, Matilde Todaro, Luca Tiberi and Alessio Zippo ()
Additional contact information
Daniela Michelatti: Computational and Integrative Biology (CIBIO), University of Trento
Sven Beyes: Computational and Integrative Biology (CIBIO), University of Trento
Chiara Bernardis: Computational and Integrative Biology (CIBIO), University of Trento
Maria Luce Negri: Computational and Integrative Biology (CIBIO), University of Trento
Leonardo Morelli: Computational and Integrative Biology (CIBIO), University of Trento
Naiara Garcia Bediaga: Computational and Integrative Biology (CIBIO), University of Trento
Vittoria Poli: Computational and Integrative Biology (CIBIO), University of Trento
Luca Fagnocchi: Computational and Integrative Biology (CIBIO), University of Trento
Sara Lago: Computational and Integrative Biology (CIBIO), University of Trento
Sarah D’Annunzio: Computational and Integrative Biology (CIBIO), University of Trento
Nicole Cona: Computational and Integrative Biology (CIBIO), University of Trento
Ilaria Gaspardo: Computational and Integrative Biology (CIBIO), University of Trento
Aurora Bianchi: Computational and Integrative Biology (CIBIO), University of Trento
Jovana Jovetic: Computational and Integrative Biology (CIBIO), University of Trento
Matteo Gianesello: Computational and Integrative Biology (CIBIO), University of Trento
Alice Turdo: Mother and Child Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo
Caterina D’Accardo: Mother and Child Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo
Miriam Gaggianesi: Oncological and Stomatological Sciences (DICHIRONS), University of Palermo
Martina Dori: University of Modena and Reggio Emilia
Mattia Forcato: University of Modena and Reggio Emilia
Giuliano Crispatzu: University of Cologne
Alvaro Rada-Iglesias: CSIC/Universidad de Cantabria
Maria Soledad Sosa: Icahn School of Medicine at Mount Sinai
H. T. Marc Timmers: Medical Center-University of Freiburg
Silvio Bicciato: University of Modena and Reggio Emilia
Matilde Todaro: Mother and Child Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo
Luca Tiberi: Computational and Integrative Biology (CIBIO), University of Trento
Alessio Zippo: Computational and Integrative Biology (CIBIO), University of Trento

Nature Communications, 2024, vol. 15, issue 1, 1-24

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-46524-0

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