Hippo signalling pathway mediates oncogenic properties of NAB2::STAT6 in solitary fibrous tumour

Solitary fibrous tumour (SFT) is a rare mesenchymal neoplasm molecularly defined by the NAB2::STAT6 gene fusion (GF), an aberrant transcriptional regulator whose functions beyond EGR1 activation remain incompletely understood. This study aimed to further elucidate the oncogenic role of NAB2::STAT6 and to identify potential therapeutic vulnerabilities. Human mesenchymal stem cell–derived SFT models (SFT-MSCs) were generated via ectopic expression of NAB2::STAT6 and analysed by gene expression microarray to assess the impact of this fusion on the transcriptomic profile. Stable SFT-MSC clones were subjected to functional assays following YAP1/TAZ silencing via siRNAs or pharmacological inhibition with dasatinib. Transcriptomic profiling of 16 tumours was performed to investigate correlations between Hippo pathway and EGR1 transcriptional signatures. Nuclear YAP1/TAZ expression was assessed by immunohistochemistry (IHC) in 44 patient samples, and genomic structural variations (SVs) were analyzed in 8 SFT specimens through Optical Genome Mapping. NAB2::STAT6 ectopic expression led to Hippo pathway dysregulation and promoted a malignant phenotype, which was partially reversible upon YAP1/TAZ knockdown or dasatinib treatment. Total RNA-seq of SFT local cases confirmed transcriptional inactivation of Hippo signalling and revealed a network linking Hippo and EGR1 pathways. Stronger nuclear YAP1/TAZ staining was observed in relapsed SFT samples compared with primary tumors. The overall genomic stability precluded Hippo pathway deregulation via SVs in clinical samples. NAB2::STAT6 promotes SFT progression by inactivating the Hippo pathway, unveiling a potential targetable vulnerability and further expanding our understanding of NAB2::STAT6-driven oncogenesis.