Abstract B42: YAP1/Hippo pathway and SWI/SNF as critical players in squamous cancers and normal development

Cancer development is a multistep process involving deregulation of transcription/epigenetic factors and signaling pathways. Accordingly, gene expression lies at the nexus of oncogenic cellular processes. The recent advent of The Cancer Genome Atlas (TCGA) has shed light on multiple genes involved in signaling, transcription, and other cellular processes that are subjected to genomic alterations in multiple cancers. These oncogenic drivers are involved in regenerative proliferation, metastasis, and other cellular processes that contribute to tumorigenesis. Epithelial-stromal interactions and the infiltrating immune response contribute significantly to tumor progression. Our recent studies revealed Hippo pathway activation as a critical component in ACTL6A (subunit of SWI/SNF chromatin remodeling complex) amplified squamous cancers. Our published genetic studies indicate that YAP is a key mediator of the oncogenic function of ACTL6A/p63 in head and neck squamous cancers. P63 is a master transcription factor in epithelial development. We have shown that YAP and p63 biochemically interact to maintain airway architecture and regeneration. YAP and p63 deletion are phenocopies and are required to maintain normal respiratory epithelial stem cells. P63/ACTL6A act as upstream regulators of YAP in squamous cancers. ACTL6A and p63 physically interact and cooperatively control a transcriptional program that promotes proliferation and suppresses differentiation, through activation of the Hippo-YAP pathway via regulators including WWC1 and GPRC5A. Consequently, loss of ACTL6A or p63 in tumor cells induces YAP phosphorylation and inactivation, associated with growth arrest and terminal differentiation, all phenocopied by WWC1 overexpression. YAP activation predicts poor patient survival in squamous cancers. These findings are also in keeping with the emerging role of the YAP pathway as a tumor driver in multiple contexts. Given interest in YAP as a therapeutic target, our studies reveal contribution of p63 and TEAD to YAP function as evident from global transcription profiling. Our most recent studies also indicate contribution of YAP in tumor progression by evading host immune response. All these indicate an important intrinsic role of YAP in development and disease, making it one of the ideal therapeutic targets to control cancer. Citation Format: Leif Ellisen, Purushothama Rao Tata, Rui Zhao, Jayaraj Rajagopal, Srinivas Vinod Saladi. YAP1/Hippo pathway and SWI/SNF as critical players in squamous cancers and normal development [abstract]. In: Proceedings of the AACR Special Conference on the Hippo Pathway: Signaling, Cancer, and Beyond; 2019 May 8-11; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(8_Suppl):Abstract nr B42.