Mutant CFTR Drives TWIST1 mediated epithelial-mesenchymal transition

Area of Science:

• Cell Biology
• Genetics
• Oncology

Background:

• Cystic fibrosis (CF) is a genetic disorder caused by mutations in the CFTR gene.
• CFTR dysfunction is linked to processes beyond ion transport, including development and wound healing.
• CFTR's proposed tumor suppressor role and association with epithelial-mesenchymal transition (EMT) in cancer warrant investigation.

Purpose of the Study:

• To determine if EMT is active in CF airways and if it's caused by CFTR mutations.
• To investigate the molecular mechanisms linking mutant CFTR to EMT.
• To assess the reversibility of CF-associated EMT using CFTR modulators.

Main Methods:

• Analysis of epithelial and mesenchymal markers and EMT-associated transcription factors in CF tissues and cells.
• Measurement of transepithelial electrical resistance, proliferation, and regeneration rates.
• Assessment of CF cell sensitivity to TGF-β1-induced EMT and response to CFTR modulators.

Main Results:

• CF tissues and cells with mutant CFTR exhibit signs of active EMT, including disrupted epithelial structures and increased mesenchymal markers.
• Mutant CFTR-induced EMT is mediated by the transcription factor TWIST1.
• CF cells are hypersensitive to EMT, but this phenotype is reversible with CFTR modulator drugs.

Conclusions:

• EMT is intrinsically triggered by the absence of functional CFTR via a TWIST1-dependent mechanism.
• CFTR plays a direct role in protecting against EMT.
• This link provides a mechanism for the high incidence of fibrosis and cancer in CF and supports CFTR's tumor suppressor function.