J Cyst Fibros. 2026 Sep 12:S1569-1993(26)03734-3. doi: 10.1016/j.jcf.2026.08.012. Online ahead of print.
ABSTRACT
BACKGROUND: People with cystic fibrosis (PwCF) have an increased risk of pancreatic cancer, likely related to chronic pancreatic inflammation and CFTR dysfunction. With the widespread use of CFTR modulators such as elexacaftor/tezacaftor/ivacaftor (ETI), understanding their impact on pancreatic ductal cell biology is critical.
METHODS: We studied human pancreatic ductal adenocarcinoma cell lines (PANC-1, CFPAC-1) and primary pig pancreatic duct epithelial cells with wild-type, F508del, or null CFTR. CFTR function was restored using adenoviral transfection (Ad5CMVCFTR-GFP) or ETI treatment. Proliferation was monitored longitudinally; cell cycle kinetics and active DNA synthesis were analyzed via Brdu/propidium iodide flow cytometry; cellular motility was assessed via scratch wound healing assays; apoptosis was measured by flow cytometry; CFTR activity was evaluated using halide-sensitive YFP; and gene expression was assessed by RT-qPCR and RNA sequencing. Human pancreas cancer CFTR expression was evaluated using public datasets.
RESULTS: CFTR expression was reduced in pancreas cancer tissues, cell lines, and CF pancreatic duct epithelial cells compared to controls. CFTR-deficient cells exhibited increased baseline proliferation and migration. ETI treatment dynamically downshifted cell cycle distribution kinetics, without affecting apoptosis. Transcriptomic analysis revealed ETI downregulated key cell cycle regulators (CCNDs, CDKs, MCMs) and suppressed Wnt pathway activators while upregulating inhibitors, consistent with growth restriction.
CONCLUSIONS: CFTR restoration not only improves channel function but also reprograms transcriptional networks to act as a synchronized brake on epithelial replication velocity and migration. These findings suggest that CFTR-targeting therapies may fundamentally influence pancreatic cancer biology and have implications for cancer risk management in PwCF.
PMID:42731950 | DOI:10.1016/j.jcf.2026.08.012
