Barbosa, Ines, Gopalakrishnan, Rajaraman, Mercan, Samuele, Mourikis, Thanos, Martin, Typhaine, Wengert, Simon, Sheng, Caibin, Ji, Fei, Lopes, Rui, Knehr, Judith, Altorfer, Marc, Lindeman, Alicia, Russ, Carsten, Naumann, Ulrike, Golji, Javad, Sprouffske, Kathleen, Barys, Louise, Schmelzle, Tobias and Galli, Giorgio (2022) Large-scale functional epigenomic screens reveal cancer lineage-specific regulation of YAP responsive elements. Nature Communications.

Abstract

YAP and TAZ are potent transcriptional co-factors engaging TEAD proteins downstream of Hippo signaling. Malignant pleural mesothelioma (MPM) and uveal melanoma (UM) are distinct cancer lineages bearing different genetic aberrations that ultimately lead to YAP activation. Here we use MPM and UM as prototypical cancers displaying, respectively, Hippo-dependent and -independent YAP activation to demonstrate that, while YAP is essential in both diseases, its interaction with TEAD is dispensable in UM, potentially limiting the application of TEAD inhibitors. Large scale functional epigenomic screens of YAP regulatory elements in MPM and UM reveal: 1) lineage-specific enhancers controlling broad oncogene dependencies (e.g., MYC) in both diseases, 2) rewiring of MAPK transcriptional regulatory networks in MPM, translating into synergistic efficacy of TEAD and MAPK inhibitors and 3) enrichment of melanocytic master regulators at functional YREs in UM. Our work prompts the design of tailored therapeutic strategies to inhibit YAP signaling in specific cancers.

Item Type:	Article
Date Deposited:	16 Sep 2022 00:45
Last Modified:	16 Sep 2022 00:46
URI:	https://oak.novartis.com/id/eprint/47866