Breaking the redundancy: TAZ outperforms YAP1 in GIST progression

Abstract

BackgroundGastrointestinal stromal tumors (GIST) are mainly caused by gain-of-function mutations in KIT or PDGFRA genes and are the most common neoplasms of the digestive tract. Imatinib (IM), a tyrosine kinase inhibitor (TKI) targeting these oncogenic drivers, has considerably improved patient outcomes, although resistance remains a major challenge. The transcriptional co-activators YAP1 and TAZ, downstream effectors of the Hippo pathway, have emerged as potential oncogenic drivers in various cancers, including GIST. However, their specific roles in KIT-dependent tumor development remain unclear. MethodsWe used WRAP5-based nanoparticles loaded with specifically designed siRNA to selectively silence YAP1 and/or TAZ proteins in KIT-dependent IM-sensitive GIST cell lines. This nucleic acid delivery system enabled efficient and specific knockdown without cytotoxicity. We assessed the impact on cell proliferation, migration, and gene expression, focusing on YAP1/TAZ targets CYR61 and CTGF. ResultsTAZ silencing resulted in a substantial reduction in GIST-T1 cell proliferation and migration, whereas YAP1 knockdown was comparatively limited. This finding was consistent with an increased TAZ expression in GIST patients, which was associated with shorter progression-free survival and an increased tendency for metastasis development. A slight additive effect was observed upon a combined YAP1/TAZ silencing in the migration assay, suggesting a more complex regulation between these two proteins. CYR61 and CTGF expressions were predominantly regulated by TAZ, though a stronger downregulation was observed upon dual knockdown in a subset of GIST cell lines with differential YAP1 and TAZ basal expression. Finally, CYR61 seemed to be more implicated in cell proliferation inhibition, which is further supported by the correlation between high CYR61 expression and poor prognosis in the GIST patients. ConclusionOur results highlight the central regulatory function of TAZ-CYR61 axis in oncogenic processes in KIT-dependent GIST, with a modest contribution from YAP1. Targeting TAZ, alone or in combination with YAP1, may represent a promising therapeutic approach, particularly in the context of tumor heterogeneity.