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Background <p>Gastrointestinal stromal tumors (GIST) are mainly caused by gain-of-function mutations in KIT or PDGFRA genes and constitute the most common malignant neoplasm of mesenchymal origin. Dysregulation of the Hippo pathway and its downstream effectors YAP1 and TAZ has been implicated in GIST progression, yet their individual contributions remain unclear. Given emerging evidence of non‑redundant YAP1/TAZ functions in cancer, we sought to dissect their respective roles in GIST tumorigenic properties.</p> Methods <p>We developed sequence‑specific siRNAs targeting YAP1 or TAZ, individually or in combination, and delivered them into GIST-T1, GIST‑430, and GIST‑882 cells using WRAP5 peptide‑based nanoparticles. Silencing efficiency and specificity were confirmed by Western blot, RT-qPCR, and immunofluorescence. Functional assays, including wound healing, Transwell migration, MTT metabolic activity, and cell counting, were used to evaluate proliferation and migration. Downstream transcriptional targets (CYR61, CTGF) and signaling proteins (KIT/AKT/ERK pathways) were quantified. Clinical relevance was assessed using progression‑free survival and metastasis data from the ATGsarc GIST cohort.</p> Results <p>WRAP5 nanoparticles enabled specific and efficient knockdown of YAP1, TAZ, or both, with no cytotoxicity. Across GIST cell lines, TAZ silencing consistently reduced migration and proliferation, whereas YAP1 knockdown had minimal or cell-line-dependent effects. TAZ depletion markedly downregulated CYR61 and CTGF expression, while YAP1 silencing showed limited impact. CYR61 knockdown impaired proliferation and migration in all models, identifying it as a key mediator of TAZ-driven oncogenicity. Clinical analysis confirmed that high TAZ and high CYR61 expression were associated with shorter disease-free survival and metastasis.</p> Conclusion <p>TAZ, more than YAP1, acts as a major regulator of GIST proliferation and migration through transcriptional control of CYR61. These findings highlight TAZ as a promising therapeutic target and demonstrate the utility of WRAP5-based nanoparticles for selective gene silencing in GIST.</p>

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Different contributions of YAP1 and TAZ in the regulation of GIST tumorigenic properties

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月24日

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  • Irène Pezzati,
  • Thania Hammoum,
  • Clémentine Ayélé Teko-Agbo,
  • Karidia Konate,
  • Mathieu Beranger,
  • Eric Vivès,
  • Frédéric Chibon,
  • Sandrine Faure,
  • Pascal de Santa Barbara,
  • César Serrano,
  • Sébastien Deshayes,
  • Prisca Boisguérin

摘要

Background

Gastrointestinal stromal tumors (GIST) are mainly caused by gain-of-function mutations in KIT or PDGFRA genes and constitute the most common malignant neoplasm of mesenchymal origin. Dysregulation of the Hippo pathway and its downstream effectors YAP1 and TAZ has been implicated in GIST progression, yet their individual contributions remain unclear. Given emerging evidence of non‑redundant YAP1/TAZ functions in cancer, we sought to dissect their respective roles in GIST tumorigenic properties.

Methods

We developed sequence‑specific siRNAs targeting YAP1 or TAZ, individually or in combination, and delivered them into GIST-T1, GIST‑430, and GIST‑882 cells using WRAP5 peptide‑based nanoparticles. Silencing efficiency and specificity were confirmed by Western blot, RT-qPCR, and immunofluorescence. Functional assays, including wound healing, Transwell migration, MTT metabolic activity, and cell counting, were used to evaluate proliferation and migration. Downstream transcriptional targets (CYR61, CTGF) and signaling proteins (KIT/AKT/ERK pathways) were quantified. Clinical relevance was assessed using progression‑free survival and metastasis data from the ATGsarc GIST cohort.

Results

WRAP5 nanoparticles enabled specific and efficient knockdown of YAP1, TAZ, or both, with no cytotoxicity. Across GIST cell lines, TAZ silencing consistently reduced migration and proliferation, whereas YAP1 knockdown had minimal or cell-line-dependent effects. TAZ depletion markedly downregulated CYR61 and CTGF expression, while YAP1 silencing showed limited impact. CYR61 knockdown impaired proliferation and migration in all models, identifying it as a key mediator of TAZ-driven oncogenicity. Clinical analysis confirmed that high TAZ and high CYR61 expression were associated with shorter disease-free survival and metastasis.

Conclusion

TAZ, more than YAP1, acts as a major regulator of GIST proliferation and migration through transcriptional control of CYR61. These findings highlight TAZ as a promising therapeutic target and demonstrate the utility of WRAP5-based nanoparticles for selective gene silencing in GIST.