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Epigenomic landscape of human colorectal cancer unveils an aberrant core of pan-cancer enhancers orchestrated by YAP/TAZ

Author

Listed:
  • Giulia Chiara

    (IFOM, the FIRC Institute of Molecular Oncology
    Istituto Nazionale Genetica Molecolare INGM ‘Romeo ed Enrica Invernizzi’
    University of Milan
    Università degli Studi di Milano)

  • Federica Gervasoni

    (IFOM, the FIRC Institute of Molecular Oncology
    Istituto Nazionale Genetica Molecolare INGM ‘Romeo ed Enrica Invernizzi’
    University of Milan
    Università degli Studi di Milano)

  • Michaela Fakiola

    (IFOM, the FIRC Institute of Molecular Oncology
    Istituto Nazionale Genetica Molecolare INGM ‘Romeo ed Enrica Invernizzi’)

  • Chiara Godano

    (Istituto Nazionale Genetica Molecolare INGM ‘Romeo ed Enrica Invernizzi’
    University of Milan
    Università degli Studi di Milano)

  • Claudia D’Oria

    (IFOM, the FIRC Institute of Molecular Oncology
    Istituto Nazionale Genetica Molecolare INGM ‘Romeo ed Enrica Invernizzi’
    University of Milan
    Università degli Studi di Milano)

  • Luca Azzolin

    (University of Padua)

  • Raoul Jean Pierre Bonnal

    (IFOM, the FIRC Institute of Molecular Oncology
    Istituto Nazionale Genetica Molecolare INGM ‘Romeo ed Enrica Invernizzi’)

  • Giulia Moreni

    (Istituto Nazionale Genetica Molecolare INGM ‘Romeo ed Enrica Invernizzi’
    Amsterdam University Medical Center, University of Amsterdam)

  • Lorenzo Drufuca

    (IFOM, the FIRC Institute of Molecular Oncology
    Istituto Nazionale Genetica Molecolare INGM ‘Romeo ed Enrica Invernizzi’)

  • Grazisa Rossetti

    (IFOM, the FIRC Institute of Molecular Oncology
    Istituto Nazionale Genetica Molecolare INGM ‘Romeo ed Enrica Invernizzi’)

  • Valeria Ranzani

    (Istituto Nazionale Genetica Molecolare INGM ‘Romeo ed Enrica Invernizzi’)

  • Ramona Bason

    (IFOM, the FIRC Institute of Molecular Oncology
    Istituto Nazionale Genetica Molecolare INGM ‘Romeo ed Enrica Invernizzi’
    Università degli Studi di Milano)

  • Marco Simone

    (Istituto Nazionale Genetica Molecolare INGM ‘Romeo ed Enrica Invernizzi’
    University of California)

  • Francesco Panariello

    (Università degli Studi di Milano
    Telethon Institute of Genetics and Medicine TIGEM)

  • Ivan Ferrari

    (Università degli Studi di Milano)

  • Tanya Fabbris

    (Istituto Nazionale Genetica Molecolare INGM ‘Romeo ed Enrica Invernizzi’)

  • Francesca Zanconato

    (University of Padua)

  • Mattia Forcato

    (University of Modena and Reggio Emilia)

  • Oriana Romano

    (University of Modena and Reggio Emilia)

  • Jimmy Caroli

    (University of Modena and Reggio Emilia)

  • Paola Gruarin

    (Istituto Nazionale Genetica Molecolare INGM ‘Romeo ed Enrica Invernizzi’)

  • Maria Lucia Sarnicola

    (Istituto Nazionale Genetica Molecolare INGM ‘Romeo ed Enrica Invernizzi’)

  • Michelangelo Cordenonsi

    (University of Padua)

  • Alberto Bardelli

    (FPO - IRCCS
    University of Torino)

  • Nicola Zucchini

    (San Gerardo Hospital)

  • Andrea Pisani Ceretti

    (UO Chirurgia Epatobiliopancreatica e Digestiva Ospedale San Paolo)

  • Nicolò Maria Mariani

    (UO Chirurgia Epatobiliopancreatica e Digestiva Ospedale San Paolo)

  • Andrea Cassingena

    (Grande Ospedale Metropolitano Niguarda)

  • Andrea Sartore-Bianchi

    (Grande Ospedale Metropolitano Niguarda
    University of Milan)

  • Giuseppe Testa

    (University of Milan
    University of Milan
    European Institute of Oncology, IRCCS)

  • Luca Gianotti

    (Milano-Bicocca University, and Department of Surgery, San Gerardo Hospital)

  • Enrico Opocher

    (UO Chirurgia Epatobiliopancreatica e Digestiva Ospedale San Paolo
    Università degli Studi di Milano)

  • Federica Pisati

    (Histopathology Unit, Cogentech)

  • Claudio Tripodo

    (University of Palermo
    IFOM, FIRC Institute of Molecular Oncology)

  • Giuseppe Macino

    (La Sapienza University of Rome)

  • Salvatore Siena

    (Grande Ospedale Metropolitano Niguarda
    University of Milan)

  • Silvio Bicciato

    (University of Modena and Reggio Emilia)

  • Stefano Piccolo

    (IFOM, the FIRC Institute of Molecular Oncology
    University of Padua)

  • Massimiliano Pagani

    (IFOM, the FIRC Institute of Molecular Oncology
    Istituto Nazionale Genetica Molecolare INGM ‘Romeo ed Enrica Invernizzi’
    University of Milan
    Università degli Studi di Milano)

Abstract

Cancer is characterized by pervasive epigenetic alterations with enhancer dysfunction orchestrating the aberrant cancer transcriptional programs and transcriptional dependencies. Here, we epigenetically characterize human colorectal cancer (CRC) using de novo chromatin state discovery on a library of different patient-derived organoids. By exploring this resource, we unveil a tumor-specific deregulated enhancerome that is cancer cell-intrinsic and independent of interpatient heterogeneity. We show that the transcriptional coactivators YAP/TAZ act as key regulators of the conserved CRC gained enhancers. The same YAP/TAZ-bound enhancers display active chromatin profiles across diverse human tumors, highlighting a pan-cancer epigenetic rewiring which at single-cell level distinguishes malignant from normal cell populations. YAP/TAZ inhibition in established tumor organoids causes extensive cell death unveiling their essential role in tumor maintenance. This work indicates a common layer of YAP/TAZ-fueled enhancer reprogramming that is key for the cancer cell state and can be exploited for the development of improved therapeutic avenues.

Suggested Citation

  • Giulia Chiara & Federica Gervasoni & Michaela Fakiola & Chiara Godano & Claudia D’Oria & Luca Azzolin & Raoul Jean Pierre Bonnal & Giulia Moreni & Lorenzo Drufuca & Grazisa Rossetti & Valeria Ranzani , 2021. "Epigenomic landscape of human colorectal cancer unveils an aberrant core of pan-cancer enhancers orchestrated by YAP/TAZ," Nature Communications, Nature, vol. 12(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-22544-y
    DOI: 10.1038/s41467-021-22544-y
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    Cited by:

    1. Maura Galimberti & Maria R. Nucera & Vittoria D. Bocchi & Paola Conforti & Elena Vezzoli & Matteo Cereda & Camilla Maffezzini & Raffaele Iennaco & Andrea Scolz & Andrea Falqui & Chiara Cordiglieri & M, 2024. "Huntington’s disease cellular phenotypes are rescued non-cell autonomously by healthy cells in mosaic telencephalic organoids," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    2. Royce W. Zhou & Jia Xu & Tiphaine C. Martin & Alexis L. Zachem & John He & Sait Ozturk & Deniz Demircioglu & Ankita Bansal & Andrew P. Trotta & Bruno Giotti & Berkley Gryder & Yao Shen & Xuewei Wu & S, 2022. "A local tumor microenvironment acquired super-enhancer induces an oncogenic driver in colorectal carcinoma," Nature Communications, Nature, vol. 13(1), pages 1-17, December.

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