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

Cancer Cell. 2021 Aug 9;39(8):1115-1134.e12. doi: 10.1016/j.ccell.2021.06.016. Epub 2021 Jul 21.


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.

Keywords: RB1; TAZ/WWTR1; TEAD; YAP; cancer plasticity; cancer stratification; neuroendocrine cancer; retinoblastoma; retinoma; small cell cancers.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Cell Line, Tumor
  • Enhancer Elements, Genetic
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Integrins / metabolism
  • Lung Neoplasms / genetics*
  • Male
  • Mice, Transgenic
  • Prostatic Neoplasms / genetics
  • Prostatic Neoplasms / pathology
  • Retinal Neoplasms / genetics
  • Retinal Neoplasms / pathology
  • Retinoblastoma / genetics
  • Retinoblastoma / pathology
  • Retinoblastoma Binding Proteins / genetics
  • Small Cell Lung Carcinoma / genetics*
  • TEA Domain Transcription Factors / genetics*
  • TEA Domain Transcription Factors / metabolism
  • Transcriptional Coactivator with PDZ-Binding Motif Proteins / genetics*
  • Ubiquitin-Protein Ligases / genetics
  • Xenograft Model Antitumor Assays
  • YAP-Signaling Proteins / genetics*


  • Antineoplastic Agents
  • Integrins
  • RB1 protein, human
  • Retinoblastoma Binding Proteins
  • TEA Domain Transcription Factors
  • Transcriptional Coactivator with PDZ-Binding Motif Proteins
  • WWTR1 protein, human
  • YAP-Signaling Proteins
  • YAP1 protein, human
  • Ubiquitin-Protein Ligases