Salk Institute Organoids Identify CFTR as Chronic Pancreatitis Target

Chronic pancreatitis remains a challenging condition for approximately three million people worldwide, characterized by persistent inflammation, scarring, and pain. Because there is currently no cure, the disease is often difficult to manage once it takes hold. To address this, a team at the Salk Institute has created a new organoid platform that allows scientists to model the disease in human cells for the first time. Over the last decade, organoids have become a prevalent tool to bridge the gap between cell and human studies. Each organoid typically begins with stem or progenitor cells from patients, and in the lab of Dannielle Engle, PhD, donor pancreas tissues were used to create these miniature replicas of the pancreas.

Mapping Molecular Drivers in 37 Patient Organoids

To build a model that reflects the complexity of the disease, researchers generated 37 organoids derived from patients with various forms of chronic pancreatitis, including those with spontaneous, alcohol-related, and genetic origins. This diversity was essential, as the team sought to understand why patients with the same clinical diagnosis often experience vastly different disease progressions. “Though patients can have the same clinical diagnosis of chronic pancreatitis, they can have very different underlying molecular drivers of that disease, which makes treatment especially difficult,” said Dannielle Engle, PhD, assistant professor at Salk and corresponding author of the study. “Our work breaks down a major barrier in the field by establishing an experimental model that preserves patient-specific disease biology and can be used to develop tailored therapies.”

The researchers surveyed the molecular signatures in each organoid and identified three distinct biological subtypes of chronic pancreatitis. This discovery suggests that future clinical approaches could shift toward classifying patients based on these molecular signatures rather than relying solely on the underlying cause of the inflammation.

CFTR Dysfunction as a Potential Treatment Target

A primary finding of the study involves the cystic fibrosis transmembrane conductance regulator (CFTR) protein. The team observed that about half of the organoids exhibited consistent dysfunction in CFTR. Crucially, this issue was not restricted to patients who carry inherited CFTR mutations. This insight indicates that standard genetic testing might overlook therapeutic opportunities for a significant portion of patients. “By growing organoids directly from patients, we preserve key features of ductal cells and ask which disease mechanisms are active in each individual patient,” said Victoria Osorio-Vasquez, PhD, a postdoctoral researcher in Engle’s lab and first author of the study. “And CFTR dysfunction was not limited to patients with inherited CFTR mutations, suggesting that functional testing may identify therapeutic opportunities that would be missed by genetic testing alone,” Osorio-Vasquez says.

By testing clinically available CFTR modulators—drugs already used to treat cystic fibrosis—the researchers found that these therapies could stabilize or restore CFTR function and reduce inflammatory signaling in responsive pancreas organoids. This suggests a potential pathway for repurposing existing medicines to offer relief for chronic pancreatitis patients.

Future Research and Biomarker Discovery

Beyond the immediate potential for new therapies, the organoid platform serves as a tool for studying disease evolution. The researchers identified rare alterations in the KRAS and TP53 genes within some samples. These findings provide a foundation for future studies into the link between chronic inflammation and the development of pancreatic cancer. The ability to grow these miniature replicas of patient tissue creates a personalized approach to medical research. “These organoids gave us a way to study chronic pancreatitis pathogenesis in human cells for the first time,” says Engle. “Our platform enables a more personalized way of studying and eventually treating chronic pancreatitis, while also blazing the trail for other organoid-based platforms in other inflammatory disease contexts.”

Readers should note that while this research offers a new experimental model for understanding disease mechanisms, it does not constitute medical advice. Patients should consult with qualified healthcare professionals regarding any existing conditions or potential treatment options.

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