TGF-β synergizes with defects in the Hippo pathway to stimulate human malignant mesothelioma growth

Area of Science:

• Oncology
• Molecular Biology
• Pathology

Background:

• Malignant mesothelioma (MM) is an aggressive cancer linked to asbestos exposure, often diagnosed late.
• The molecular drivers of MM, particularly early lesions, remain poorly understood.
• Mutations in NF2 and the Hippo signaling pathway (regulating YAP) are common in MM.

Purpose of the Study:

• To investigate the functional interaction between the Hippo and TGF-β pathways in MM.
• To elucidate the role of connective tissue growth factor (CTGF) in MM pathogenesis.
• To identify novel therapeutic targets for malignant mesothelioma.

Main Methods:

• Investigated the YAP-TEAD4-Smad3-p300 complex formation on the CTGF promoter in MM cells.
• Assessed the impact of CTGF knockdown on MM cell survival in xenograft models.
• Analyzed CTGF expression in relation to extracellular matrix deposition in patient samples.

Main Results:

• A YAP-TEAD4-Smad3-p300 complex was found to induce CTGF expression in MM cells.
• CTGF knockdown significantly improved survival in mice with MM xenografts.
• CTGF expression correlated with extracellular matrix deposition in both xenografts and human MM tissues.

Conclusions:

• CTGF is a key mediator of MM growth and pathology, influenced by the Hippo and TGF-β pathways.
• CTGF expression patterns suggest a role in mesothelioma malignancy.
• CTGF represents a promising novel therapeutic target for malignant mesothelioma.