Cancer-Associated Fibroblast-Centric Risk Model Predicts Immunotherapy Resistance in Pancreatic Cancer and Reveals...

Area of Science:

• Oncology
• Cancer Biology
• Immunology

Background:

• Pancreatic ductal adenocarcinoma (PAAD) is an aggressive malignancy.
• PAAD is characterized by cancer-associated fibroblasts (CAFs) and a complex tumor immune microenvironment.
• These factors are linked to poor patient survival, but CAF mechanisms remain unclear.

Purpose of the Study:

• To systematically analyze CAF functions in PAAD.
• To investigate CAF associations with patient outcomes.
• To identify potential therapeutic targets within CAF-related genes.

Main Methods:

• Integrative analysis of multi-omics data.
• Weighted gene co-expression and protein-protein interaction network analyses.
• Experimental validation including single-cell RNA sequencing and functional assays.

Main Results:

• Identified core CAF-related genes: COL28A1, TGFB2, TGFBI, PLOD2, COL22A1.
• High-risk group showed increased immune escape and lower immunotherapy response.
• PLOD2 promotes PAAD progression via extracellular matrix remodeling; TGFBI and PLOD2 are elevated in CAFs.
• Potential therapeutic compounds: dihydrorotenone and sorafenib.

Conclusions:

• Elucidated molecular mechanisms of CAFs in PAAD.
• Established a foundation for CAF-targeting therapies in pancreatic cancer.
• Highlighted PLOD2 as a key driver of PAAD progression.