Iowa City, Iowa – The genetic defect responsible for cystic fibrosis (CF) may also directly contribute to the development of pancreatic cancer, according to a new study conducted in cell models.
Researchers found that pancreatic cancer cells carrying CF-causing mutations grew faster and were more mobile than cancer cells without these mutations. Importantly, treatment with CFTR modulators slowed the growth of these cancer cells. The findings could help explain why people with CF have an increased risk of pancreatic cancer and may point to new approaches for prevention or treatment.
The study, titled “CFTR modulation alter pancreatic cancer cell growth and signaling: implications for cancer risk in cystic fibrosis,” was published in the Journal of Cystic Fibrosis.
CFTR mutations and pancreatic cancer
Cystic fibrosis is caused by mutations in the CFTR gene, which provides instructions for producing the CFTR protein. Under normal conditions, CFTR helps regulate the movement of salt and fluids across cell membranes and contributes to the production of mucus with a normal consistency. In people with CF, CFTR is dysfunctional or absent, resulting in abnormally thick and sticky mucus that can accumulate in organs such as the lungs and pancreas.
Previous research has shown that people with CF have a higher risk of developing pancreatic cancer than the general population. This increased risk has traditionally been attributed largely to the chronic inflammation and tissue damage caused by thick mucus in the pancreas, which may create conditions that promote abnormal cell growth.
The new study, however, suggests that CFTR mutations themselves may contribute to pancreatic cancer risk, independently of inflammation.
“Our data provide mechanistic evidence that CFTR dysfunction itself may promote proliferative [growth-driving] signaling in [pancreas] cells,” the researchers wrote.
Mutant CFTR promotes cancer cell growth
The researchers conducted a series of in vitro experiments using pancreatic cells grown in laboratory dishes. They found that pancreatic cancer cells carrying F508del, the most common CF-causing CFTR mutation, grew faster than cancer cells without the mutation.
The mutation also increased the cells’ mobility, a characteristic associated with the ability of cancer cells to invade surrounding tissue and potentially spread to other parts of the body.
Similar effects were observed in non-cancerous pancreatic cells. CFTR mutations promoted both increased growth and mobility, suggesting that loss of functional CFTR may contribute to the abnormal cellular behavior that can precede or accompany pancreatic cancer.
Additional analyses of human tumor samples provided further support for this hypothesis. The researchers found that CFTR protein expression was reduced in pancreatic cancer tissues, including tumors from people who did not have CF.
“Our study demonstrates that CFTR expression is markedly reduced in human pancreas cancer tissues and cell lines, and that pancreatic … cells exhibit a highly proliferative and motile phenotype when CFTR is absent or dysfunctional,” the researchers wrote.
CFTR modulators may slow cancer cell growth
The study also examined whether restoring CFTR function could affect pancreatic cancer cells.
CFTR modulators are medications designed to improve the function of the CFTR protein in people with specific CF-causing mutations. One widely used combination is Trikafta (elexacaftor/tezacaftor/ivacaftor), which is approved for people with F508del and other eligible CFTR mutations.
In the researchers’ cell models, treatment with Trikafta reduced the growth of pancreatic cancer cells. These findings suggest that restoring CFTR activity may counter some of the growth-promoting effects associated with dysfunctional CFTR.
“Our study is the first to demonstrate direct inhibition of cancer cell proliferation through CFTR restoration in pancreas cancer and CF pancreatic epithelial cells. These results highlight CFTR as a potential tumor suppressor and suggest that its restoration may represent a novel therapeutic strategy,” the researchers concluded.
More research is needed
Despite the promising findings, the researchers emphasized that the study was conducted in laboratory cell models. Further studies in animals and humans will be needed to determine whether the same mechanisms occur in living organisms and whether CFTR modulation can actually reduce pancreatic cancer risk or slow tumor progression.
The researchers also called for prospective studies examining pancreatic cancer outcomes in people with CF who receive Trikafta and other CFTR modulators.
“Understanding the systemic impact of CFTR modulators is critical as [people with] CF live longer and face evolving health challenges, including malignancy [cancer] risk,” they wrote.
Overall, the findings suggest that dysfunctional CFTR may play a more direct role in pancreatic cancer biology than previously recognized. If confirmed in future studies, restoring CFTR function could represent a potential strategy for reducing pancreatic cancer risk or treating tumors characterized by low or dysfunctional CFTR.
Contact
Aliye Uc
Stead Family Department of Pediatrics – University of Iowa