@article{10902/32850,
year = {2024},
url = {https://hdl.handle.net/10902/32850},
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.},
organization = {Acknowledgements: We thank the NGS facility from CIBIO for their help with EU-RNA-seq, ATAC-seq, and CUT&RUN sequencing; the imaging facility from CIBIO for SIM microscopy; the Cell Analysis and Separation facility from CIBIO for cell sorting and FACS analyses; the High Throughput Screening facility from CIBIO for the acquisition of tumor sections. We would like to thank the members of the Tiberi and Zippo labs for helpful discussion and critical reading of the manuscript. We thank the Cusanelli lab for supporting us with the smRNA-FISH methodology. We thank Dr. Ron Vale for sharing the pHRdSV40-dCas9-10xGCN4_v4-P2A-BFP construct, Dr. Sakari Vanharanta for sharing the pKLV-U6gRNA(BbsI)-PGKpuro2A-BFP construct, Dr. Kenneth S. Zaret for TOPO spike-in plasmids and Dr. Federica Facciotti for sharing the NK-92 cell line. Work in the Zippo group was supported by grants from the AIRC foundation (IG 2019- 22911) and European Union under the Horizon 2020 Framework Pro[1]gramme H2020 Future and Emerging Technologies (801336; - PRO-CHIP). 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).},
publisher = {Nature Publishing Group},
publisher = {Nature Communications, 2024, 15, 2198},
title = {Oncogenic enhancers prime quiescent metastatic cells to escape NK immune surveillance by eliciting transcriptional memory},
author = {Michelatti, Daniela and Beyes, Sven and Bernardis, Chiara and Negri, Maria Luce and Morelli, Leonardo and Garcia Bediaga, Naiara and Poli, Vittoria and Fagnocchi, Luca and Lago, Sara and D'Annunzio, Sarah and Cona, Nicole and Gaspardo, Ilaria and Bianchi, Aurora and Jovetic, Jovana and Gianesello, Matteo and Turdo, Alice and D'Accardo, Caterina and Gaggianesi, Miriam and Rada Iglesias, Álvaro},
}