2. Academic Validation
  3. Oncogenic enhancers prime quiescent metastatic cells to escape NK immune surveillance by eliciting transcriptional memory

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

  • Nat Commun. 2024 Mar 19;15(1):2198. doi: 10.1038/s41467-024-46524-0.
Daniela Michelatti 1,  Sven Beyes 1,  Chiara Bernardis 1,  Maria Luce Negri 1,  Leonardo Morelli 1,  Naiara Garcia Bediaga 1 2,  Vittoria Poli 1 3,  Luca Fagnocchi 1 4,  Sara Lago 1,  Sarah D'Annunzio 1,  Nicole Cona 1,  Ilaria Gaspardo 1,  Aurora Bianchi 1,  Jovana Jovetic 1,  Matteo Gianesello 1,  Alice Turdo 5,  Caterina D'Accardo 5,  Miriam Gaggianesi 6,  Martina Dori 7,  Mattia Forcato 7,  Giuliano Crispatzu 8,  Alvaro Rada-Iglesias 9,  Maria Soledad Sosa 10,  H T Marc Timmers 11 12,  Silvio Bicciato 7,  Matilde Todaro 5,  Luca Tiberi 1,  Alessio Zippo 13
Affiliations

Affiliations

  • 1 Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, 38123, Trento, Italy.
  • 2 The South Australian Immunogenomics Cancer Institute, Faculty of Medicine Nursing and Medical Sciences, The University of Adelaide, Adelaide, Australia.
  • 3 Istituto Italiano di Tecnologia IIT, Milan, Italy.
  • 4 Department of Epigenetics Van Andel Institute, Grand Rapids, MI, USA.
  • 5 Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, Palermo, Italy.
  • 6 Department of Surgical, Oncological and Stomatological Sciences (DICHIRONS), University of Palermo, Palermo, Italy.
  • 7 Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy.
  • 8 Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.
  • 9 Institute of Biomedicine and Biotechnology of Cantabria (IBBTEC), CSIC/Universidad de Cantabria, Santander, Spain.
  • 10 Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 11 Department of Urology, Medical Center-University of Freiburg, Freiburg, Germany.
  • 12 German Cancer Consortium (DKTK) partner site Freiburg, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany.
  • 13 Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, 38123, Trento, Italy. alessio.zippo@unitn.it.
PMID: 38503727 DOI: 10.1038/s41467-024-46524-0
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.

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