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

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, Ramona Bason, Marco Simone, Francesco Panariello, Ivan Ferrari, Tanya Fabbris, Francesca Zanconato, Mattia Forcato, Oriana Romano, Jimmy Caroli, Paola Gruarin, Maria Lucia Sarnicola, Michelangelo Cordenonsi, Alberto Bardelli, Nicola Zucchini, Andrea Pisani Ceretti, Nicolò Maria Mariani, Andrea Cassingena, Andrea Sartore-Bianchi, Giuseppe Testa, Luca Gianotti, Enrico Opocher, Federica Pisati, Claudio Tripodo, Giuseppe Macino, Salvatore Siena, Silvio Bicciato, Stefano Piccolo () and Massimiliano Pagani ()
Additional contact information
Giulia Chiara: IFOM, the FIRC Institute of Molecular Oncology
Federica Gervasoni: IFOM, the FIRC Institute of Molecular Oncology
Michaela Fakiola: IFOM, the FIRC Institute of Molecular Oncology
Chiara Godano: Istituto Nazionale Genetica Molecolare INGM ‘Romeo ed Enrica Invernizzi’
Claudia D’Oria: IFOM, the FIRC Institute of Molecular Oncology
Luca Azzolin: University of Padua
Raoul Jean Pierre Bonnal: IFOM, the FIRC Institute of Molecular Oncology
Giulia Moreni: Istituto Nazionale Genetica Molecolare INGM ‘Romeo ed Enrica Invernizzi’
Lorenzo Drufuca: IFOM, the FIRC Institute of Molecular Oncology
Grazisa Rossetti: IFOM, the FIRC Institute of Molecular Oncology
Valeria Ranzani: Istituto Nazionale Genetica Molecolare INGM ‘Romeo ed Enrica Invernizzi’
Ramona Bason: IFOM, the FIRC Institute of Molecular Oncology
Marco Simone: Istituto Nazionale Genetica Molecolare INGM ‘Romeo ed Enrica Invernizzi’
Francesco Panariello: Università degli Studi di Milano
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
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
Giuseppe Testa: University of Milan
Luca Gianotti: Milano-Bicocca University, and Department of Surgery, San Gerardo Hospital
Enrico Opocher: UO Chirurgia Epatobiliopancreatica e Digestiva Ospedale San Paolo
Federica Pisati: Histopathology Unit, Cogentech
Claudio Tripodo: University of Palermo
Giuseppe Macino: La Sapienza University of Rome
Salvatore Siena: Grande Ospedale Metropolitano Niguarda
Silvio Bicciato: University of Modena and Reggio Emilia
Stefano Piccolo: IFOM, the FIRC Institute of Molecular Oncology
Massimiliano Pagani: IFOM, the FIRC Institute of Molecular Oncology

Nature Communications, 2021, vol. 12, issue 1, 1-18

Abstract: 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.

Date: 2021
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-22544-y

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DOI: 10.1038/s41467-021-22544-y

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