Patient-derived organoids reveal ductal dysfunction and CFTR-modulator responses in chronic pancreatitis.

Summary

This study established a 37-patient PDO platform for chronic pancreatitis, identifying three molecular subtypes and widespread CFTR dysfunction, including in cases without CFTR mutations. Clinically available CFTR modulators restored CFTR function and dampened mitogenic/inflammatory signaling, positioning CFTR modulation as a precision therapeutic strategy in chronic pancreatitis.

Key Findings

• Developed a PDO platform from 37 chronic pancreatitis patients capturing inflammation-associated molecular features.
• Identified three CP molecular subtypes independent of etiology.
• Discovered widespread CFTR dysfunction in ~50% of PDOs, including those with wild-type CFTR.
• Clinically available CFTR modulators restored CFTR function and reduced mitogenic and inflammatory signaling in PDOs.

Clinical Implications

CFTR modulators, already approved for cystic fibrosis, may be repurposed for selected chronic pancreatitis patients with demonstrated CFTR dysfunction, guiding individualized therapy using organoid testing.

Limitations

• Ex vivo organoid responses may not fully predict in vivo clinical efficacy and safety.
• Long-term clinical outcomes with CFTR modulators in chronic pancreatitis were not assessed.

Future Directions

Prospective, organoid-guided clinical trials to test CFTR modulators in molecularly selected chronic pancreatitis subgroups; exploration of combination strategies to modulate inflammatory and mitogenic pathways.