YAP/TAZ cooperate with AP-1 to drive the mesenchymal cell state in neuroblastoma [CnR]

Cellular plasticity is a major driver of therapy resistance in cancer. For the pediatric solid tumor neuroblastoma, two distinct tumor cell phenotypes have been identified: adrenergic (ADR) and mesenchymal (MES) cells. Of those, the MES cells pose a rare subtype resistant to common treatment options. Here, we developed an image-based compound screen to interrogate vulnerabilities specific to the MES phenotype at single-cell resolution in heterogeneous neuroblastoma cultures. Among the top hits, we identified inhibition of the transcriptional co-activators YAP/TAZ as a specific target in MES cells. Based on their chromatin binding, we show that YAP/TAZ cooperate with AP-1 transcription factors to regulate MES gene expression by forming a core-regulatory circuitry. We further provide evidence of a subset of tumor cells in patients co-expressing these factors. Collectively, we demonstrate that YAP/TAZ and AP-1 drive neuroblastoma tumor cell plasticity and present a novel therapeutic vulnerability with the potential to overcome treatment resistance. Overall design: We separated 2 heterogeneous neuroblastoma cell lines into adrenergic (ADR) and mesenchymal (MES) subcultures based on adherence properties. The following cell lines were used: CLB-Ma and SK-N-SH. From these 4 cultures we isolated nuclei and performed Cut&Run using the following antibodies: YAP1, WWTR1, JUN, H3K27Ac, H3K4me1, IgG