YAPTAZ and neuroblastoma cell plasticity [ChIP-seq]

High-risk neuroblastoma is a pediatric malignancy marked by poor prognosis, high metastatic potential, and resistance to conventional therapies. Phenotypic plasticity between noradrenergic and mesenchymal cell states, each defined by specific transcriptional and epigenetic programs and distinct cellular properties, is observed in some neuroblastoma cell lines. Yet the drivers of this plasticity are not fully understood. This study identifies YAP and TAZ as central regulators of the mesenchymal state. YAP/TAZ, in complex with TEAD, FOSL, and RUNX transcription factors, establish a core regulatory circuitry associated with mesenchymal-specific super-enhancers. Expression of a conserved YAP/TAZ gene signature increases during the noradrenergic-to-mesenchymal transition and decreases during the reverse in plasticity models. Genetic or pharmacological inactivation of YAP/TAZ abrogates cellular proliferation and inhibits the noradrenergic-to-mesenchymal transition. Conversely, overexpression of YAP/TAZ in noradrenergic cells induces a major transcriptional reprogramming towards a mesenchymal state, via a redistribution of TEAD4 and a rewiring of the epigenetic landscape. These findings uncover a YAP/TAZ-TEAD4 driven epigenetic mechanism underlying tumor cell plasticity in neuroblastoma.