TWEAK/Fn14 Signalling Regulates the Tissue Microenvironment in Chronic Pancreatitis

Area of Science:

• Gastroenterology and Hepatology
• Oncology
• Molecular Biology

Background:

• Chronic pancreatitis elevates pancreatic cancer risk by promoting proliferation, fibrosis, and inflammation.
• The tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK)/fibroblast growth factor-inducible 14 (Fn14) pathway regulates cellular processes in chronic liver injury.
• The role of the TWEAK/Fn14 pathway in pancreatic disease remains uncharacterized.

Purpose of the Study:

• To investigate the role of the TWEAK/Fn14 signaling pathway in chronic pancreatitis.
• To determine if TWEAK/Fn14 signaling influences pancreatic ductal proliferation, fibrosis, and inflammation.
• To evaluate the TWEAK/Fn14 pathway as a potential therapeutic target for pancreatic disease.

Main Methods:

• Analysis of public datasets to assess Fn14 expression in pancreatitis and pancreatic adenocarcinoma.
• Single-cell RNA sequencing to identify Fn14-producing cells.
• Choline-deficient, ethionine-supplemented (CDE) diet model in wildtype and Fn14 knockout mice to study pancreatitis progression.

Main Results:

• Fn14 is upregulated in pancreatitis and pancreatic adenocarcinoma, primarily in pancreatic ductal cells.
• Absence of TWEAK/Fn14 signaling significantly inhibited the development and progression of chronic pancreatitis in the CDE model.
• Key pathological features including pancreatic ductal proliferation, fibrosis, and inflammation were reduced in Fn14 knockout mice.

Conclusions:

• The TWEAK/Fn14 signaling pathway is a critical regulator of chronic pancreatitis pathogenesis.
• Targeting the TWEAK/Fn14 pathway holds promise for preventing or treating chronic pancreatitis and potentially pancreatic cancer.
• Fn14 is identified as a novel therapeutic target in pancreatic ductal cells.