YAPTAZ and neuroblastoma cell plasticity [RNA-Seq]

Spontaneous and reversible plasticity between two tumor cell states, noradrenergic and mesenchymal, has been described in neuroblastoma cell lines. Here, we show that YAP, TAZ, and their target genes are marked by super-enhancers and are strongly and specifically expressed in mesenchymal tumor cells. We characterize a core regulatory circuitry containing YAP/TAZ, TEAD, FOSL and RUNX factors that controls gene expression linked to a mesenchymal identity in neuroblastoma. Genetic or pharmacological inactivation of YAP/TAZ reduces cell proliferation of mesenchymal neuroblastoma cells. The expression of a YAP/TAZ gene signature fully correlates with a mesenchymal identity in several models exhibiting plasticity between noradrenergic and mesenchymal states. Whereas YAP/TAZ inhibition impairs the noradrenergic to mesenchymal transition, YAP and/or TAZ overexpression induces a mesenchymal shift traduced by transcriptional and functional reprogramming, accompanied by the repression of noradrenergic identity. Altogether, these findings uncover a neuroblastoma-specific YAP/TAZ core regulatory circuitry controlling the switch of cell state towards a mesenchymal identity in neuroblastoma.