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Purpose <p>Solitary fibrous tumour (SFT) is a rare mesenchymal neoplasm molecularly defined by the <i>NAB2::STAT6</i> gene fusion (GF), an aberrant transcriptional regulator whose functions beyond <i>EGR1</i> activation remain incompletely understood. This study aimed to further elucidate the oncogenic role of <i>NAB2::STAT6</i> and to identify potential therapeutic vulnerabilities.</p> Methods <p>Human mesenchymal stem cell–derived SFT models (SFT-MSCs) were generated via ectopic expression of <i>NAB2::STAT6</i> 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 <i>YAP1/TAZ</i> 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.</p> Results <p><i>NAB2::STAT6</i> ectopic expression led to Hippo pathway dysregulation and promoted a malignant phenotype, which was partially reversible upon <i>YAP1/TAZ</i> 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.</p> Conclusion <p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月10日

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  • Carmen Salguero-Aranda,
  • Laura Lobo-Selma,
  • Amparo Beltrán-Povea,
  • Sergio Baute-González,
  • Paula Gilabert-Prieto,
  • Carmen Jordán-Perez,
  • José Alberto Fernández-Juárez,
  • Ana Teresa Amaral,
  • René Rodríguez,
  • Juan Díaz-Martín,
  • Enrique de Álava

摘要

Purpose

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.

Methods

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.

Results

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.

Conclusion

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.