Binary pan-cancer classes with distinct vulnerabilities defined by pro- or anti-cancer YAP/TEAD activity

• DOI: 10.1016/j.ccell.2021.06.016
• Publication Date: 2021-07-21T17:25:42Z
• Authors: Joel D. Pearson; Katherine Huang; Marek Pacal; Sean R. McCurdy; Suying Lu; Arthur Aubry; Tao Yu; Kristine M. Wadosky; Letian Zhang; Tao Wang; Alex Gregorieff; Mohammad Ahmad; Helen Dimaras; Ellen Langille; Susan P.C. Cole; Philippe P. Monnier; Benjamin H. Lok; Ming-Sound Tsao; Nagako Akeno; Daniel Schramek; Kathryn A. Wikenh...; Erik S. Knudsen; Agnieszka K. Witk...; Jeffrey L. Wrana; David W. Goodrich; Rod Bremner
• Keywords: Male; Integrins; 0303 health sciences; Lung Neoplasms; Retinal Neoplasms; Ubiquitin-Protein Ligases; Retinoblastoma; Prostatic Neoplasms; TEA Domain Transcription Factors; Antineoplastic Agents; Mice, Transgenic; YAP-Signaling Proteins; Small Cell Lung Carcinoma; Xenograft Model Antitumor Assays; 3. Good health; Gene Expression Regulation, Neoplastic; Retinoblastoma Binding Proteins; 03 medical and health sciences; Enhancer Elements, Genetic; Cell Line, Tumor; Transcriptional Coactivator with PDZ-Binding Motif Proteins; Animals; Humans

Cancer heterogeneity impacts therapeutic response, driving efforts to discover over-arching rules that supersede variability. Here, we define pan-cancer binary classes based on distinct expression of YAP and YAP-responsive adhesion regulators. Combining informatics with in vivo and in vitro gain- and loss-of-function studies across multiple murine and human tumor types, we show that opposite pro- or anti-cancer YAP activity functionally defines binary YAPon or YAPoff cancer classes that express or silence YAP, respectively. YAPoff solid cancers are neural/neuroendocrine and frequently RB1-/-, such as retinoblastoma, small cell lung cancer, and neuroendocrine prostate cancer. YAP silencing is intrinsic to the cell of origin, or acquired with lineage switching and drug resistance. The binary cancer groups exhibit distinct YAP-dependent adhesive behavior and pharmaceutical vulnerabilities, underscoring clinical relevance. Mechanistically, distinct YAP/TEAD enhancers in YAPoff or YAPon cancers deploy anti-cancer integrin or pro-cancer proliferative programs, respectively. YAP is thus pivotal across cancer, but in opposite ways, with therapeutic implications.