MYC-driven epigenetic reprogramming favors the onset of tumorigenesis by inducing a stem cell-like state

Vittoria Poli, Luca Fagnocchi, Alessandra Fasciani, Alessandro Cherubini, Stefania Mazzoleni, Sara Ferrillo, Annarita Miluzio, Gabriella Gaudioso, Valentina Vaira, Alice Turdo, Miriam Giaggianesi, Aurora Chinnici, Elisa Lipari, Silvio Bicciato, Silvano Bosari, Matilde Todaro, Alessio Zippo

Research output: Contribution to journalArticle

Abstract

Breast cancer consists of highly heterogeneous tumors, whose cell of origin and driver oncogenes are difficult to be uniquely defined. Here we report that MYC acts as tumor reprogramming factor in mammary epithelial cells by inducing an alternative epigenetic program, which triggers loss of cell identity and activation of oncogenic pathways. Overexpression of MYC induces transcriptional repression of lineage-specifying transcription factors, causing decommissioning of luminal-specific enhancers. MYC-driven dedifferentiation supports the onset of a stem cell-like state by inducing the activation of de novo enhancers, which drive the transcriptional activation of oncogenic pathways. Furthermore, we demonstrate that the MYC-driven epigenetic reprogramming favors the formation and maintenance of tumor-initiating cells endowed with metastatic capacity. This study supports the notion that MYC-driven tumor initiation relies on cell reprogramming, which is mediated by the activation of MYC-dependent oncogenic enhancers, thus establishing a therapeutic rational for treating basal-like breast cancers.

Original languageEnglish
Article number1024
JournalNature Communications
Volume9
Issue number1
DOIs
Publication statusPublished - Dec 1 2018

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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    Poli, V., Fagnocchi, L., Fasciani, A., Cherubini, A., Mazzoleni, S., Ferrillo, S., Miluzio, A., Gaudioso, G., Vaira, V., Turdo, A., Giaggianesi, M., Chinnici, A., Lipari, E., Bicciato, S., Bosari, S., Todaro, M., & Zippo, A. (2018). MYC-driven epigenetic reprogramming favors the onset of tumorigenesis by inducing a stem cell-like state. Nature Communications, 9(1), [1024]. https://doi.org/10.1038/s41467-018-03264-2