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

Abstract

'Chiara Godano' 'Claudia D’Oria' 'Luca Azzolin' 'Raoul Jean Pierre Bonnal' 'Giulia Moreni' 'Lorenzo Drufuca' 'Grazisa Rossetti' 'Valeria Ranzani' 'Ramona Bason' 'Marco De 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' 'Massimiliano Pagani'] 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.