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

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Cancer heterogeneity poses challenges for effective therapeutic strategies.
• Identifying overarching principles that govern cancer behavior is crucial for advancing treatment.
• The role of YAP (Yes-associated protein) in cancer is complex and context-dependent.

Purpose of the Study:

• To define pan-cancer binary classes based on YAP activity and its regulators.
• To investigate the functional consequences of distinct YAP activity states in cancer.
• To explore the therapeutic vulnerabilities associated with these binary cancer classes.

Main Methods:

• Bioinformatics analysis of gene expression data.
• In vivo and in vitro gain- and loss-of-function studies in murine and human tumor models.
• Analysis of YAP/TEAD enhancer activity and downstream gene programs.

Main Results:

• Established two binary cancer classes: YAP-ON (expressing YAP) and YAP-OFF (silencing YAP).
• YAP-OFF cancers are predominantly neural/neuroendocrine, often RB1-deficient (e.g., retinoblastoma, SCLC, NEPC).
• Distinct YAP-dependent adhesive behaviors and pharmaceutical vulnerabilities were identified for each class.
• Mechanistically, YAP/TEAD enhancers drive either anti-cancer integrin or pro-cancer proliferative programs.

Conclusions:

• YAP activity dichotomously defines fundamental cancer classes with distinct biological and clinical features.
• YAP silencing can be an intrinsic or acquired trait linked to cell of origin, lineage switching, or drug resistance.
• Understanding these binary YAP states offers novel therapeutic strategies targeting specific cancer vulnerabilities.