Cancer lineage-specific regulation of YAP responsive elements revealed through large-scale functional epigenomic screens

YAP is a key transcriptional co-activator that regulates cell growth and is frequently found activated in cancer due to mutations in upstream regulators1. The Hippo pathway represents the canonical signaling axis restraining nuclear activation of YAP and its co-activator TEAD. Malignant pleural mesothelioma (MPM) is the classic example of a YAP-TEAD driven tumor caused by inactivating mutations in upstream components of the Hippo pathway. In Uveal Melanoma (UM), however, YAP is activated in a Hippo-independent manner, due to upstream oncogenic mutations in GNAQ/GNA11 GTPases. While in different cancer lineages YAP activity can be induced by different oncogenic stimuli, to date it is unclear whether and how YAP oncogenic transcriptional program can be differentially impacted, which is particularly relevant for designing selective anti-cancer therapies. Here we show that, although YAP is essential in both MPM and UM, its interaction with TEAD is unexpectedly dispensable in UM, limiting the applicability of TEAD inhibitors in this cancer type. To systematically interrogate YAP cistrome, we employed large-scale functional epigenomic screens of YAP regulatory elements (YRE) in both cancer types. Our results reveal convergent regulation of broad oncogenic drivers (e.g. MYC) in both MPM and UM, but also strikingly selective programs, namely an MPM-specific rewiring of the MAPK transcriptional regulatory network, translating into synergy between TEAD and MAPK inhibitors, and a UM-specific engagement of melanocytic master regulators, like MITF, SOX10 and PAX3. In summary, our work reveals unanticipated lineage-specific features of the YAP regulatory network that provide important insights to guide the design of tailored therapeutic strategies to inhibit YAP signaling across different cancer types.