A regulatory circuitry driving a noradrenergic to mesenchymal transition highlights YAP/TAZ as critical players in neuroblastoma plasticity.

High-risk neuroblastoma is a pediatric cancer characterized by poor prognosis, metastases, and resistance to conventional therapies. Some neuroblastoma cell lines exhibit phenotypic plasticity between noradrenergic and mesenchymal states, each defined by distinct transcriptional and super-enhancer programs; however, the mechanisms governing this switch remain unclear. This study identifies YAP and TAZ as key regulators of the mesenchymal state. Acting with TEAD, FOSL, and RUNX transcription factors, YAP/TAZ form 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 process. Genetic or pharmacological YAP/TAZ inhibition blocks proliferation and prevents transition to the mesenchymal state. Conversely, YAP/TAZ overexpression in noradrenergic cells induces extensive transcriptional reprogramming toward a mesenchymal phenotype, driven by TEAD4 redistribution and super-enhancer rewiring. These findings reveal a YAP/TAZ-TEAD4 axis controlling tumor cell plasticity in neuroblastoma.