Epithelial FOXP3 Orchestrates O-Glycosylated IL6 Secretion to Drive Pancreatic Fibrocarcinogenesis

Area of Science:

• Oncology
• Cell Biology
• Biochemistry

Background:

• Pancreatic fibrosis is a hallmark of pancreatic ductal adenocarcinoma (PDAC), contributing to treatment resistance and organ failure.
• The mechanisms initiating fibrosis in early preneoplastic stages of PDAC are not fully understood.
• The transcription factor FOXP3 was unexpectedly found in epithelial cells of precancerous pancreatic lesions.

Purpose of the Study:

• To investigate the role of epithelial FOXP3 (E-FOXP3) in initiating pancreatic fibrosis during early preneoplastic stages.
• To elucidate the molecular mechanisms by which E-FOXP3 influences fibrogenesis and neoplasia progression.
• To assess the therapeutic potential of targeting the E-FOXP3 pathway with a fasting-mimicking diet.

Main Methods:

• Analysis of FOXP3 expression in human and murine premalignant pancreatic tissues.
• Utilizing epithelial-specific FOXP3 knockout and knock-in mouse models.
• Investigating molecular mechanisms through chromatin immunoprecipitation, glycomic analyses, and signaling assays.
• Evaluating the efficacy of a fasting-mimicking diet in vivo.

Main Results:

• E-FOXP3 expression was consistently observed in precancerous pancreatic epithelia.
• Epithelial-specific FOXP3 deletion attenuated fibrosis and delayed neoplasia, while knock-in accelerated these processes.
• E-FOXP3 transactivates GALNT1, leading to O-glycosylation of IL-6 at T165, essential for its secretion and activation of pancreatic stellate cells (PSCs) via gp130.
• This creates a self-reinforcing MAPK/ERK signaling loop that drives stromal activation and fibrotic expansion.
• A fasting-mimicking diet suppressed the E-FOXP3-GALNT1 axis, reduced IL-6 glycosylation, and ameliorated pancreatic fibrosis.

Conclusions:

• Epithelial FOXP3 is a key regulator of early pancreatic fibrocarcinogenesis.
• E-FOXP3 orchestrates sustained stromal activation through a glycosylation-dependent IL-6 signaling loop.
• Targeting the E-FOXP3-driven pathway offers a promising strategy to intercept pancreatic fibrosis and carcinogenesis at their origin.