Integrative Single-Cell and Spatial Transcriptomics Analysis Reveals ECM-remodeling Cancer-associated...

Area of Science:

• Oncology
• Cell Biology
• Bioinformatics

Background:

• Pancreatic ductal adenocarcinoma (PDAC) poses significant clinical challenges due to its dense stroma and complex tumor microenvironment (TME).
• Understanding fibroblast heterogeneity and their interactions with cancer cells is crucial for developing effective therapies.

Purpose of the Study:

• To dissect fibroblast heterogeneity and their crosstalk with epithelial cells in PDAC using integrated transcriptomic data.
• To identify key ligand-receptor interactions driving PDAC progression.
• To investigate the therapeutic potential of targeting identified pathways.

Main Methods:

• Integration of large-scale single-cell and spatial transcriptomics.
• Identification and characterization of fibroblast subpopulations.
• Analysis of ligand-receptor interactions, transcription factor roles, and pathway activation (PI3K/AKT/β-catenin).
• Clinical correlation analysis and in vitro functional assays.

Main Results:

• Eight distinct fibroblast subpopulations were identified, with ECM-remodeling fibroblasts associated with poor prognosis in PDAC.
• SOX11 was identified as a key transcription factor in ECM-remodeling fibroblasts.
• The POSTN-ITGAV/ITGB5 axis was identified as a critical ligand-receptor interaction promoting tumor progression via PI3K/AKT/β-catenin signaling and EMT.
• High POSTN expression correlated with poor prognosis in PDAC patients.
• Pharmacological inhibition of the POSTN-integrin axis partially reversed malignant phenotypes.

Conclusions:

• Fibroblast heterogeneity plays a significant role in PDAC progression.
• The POSTN-ITGAV/ITGB5 axis represents a promising therapeutic target for pancreatic ductal adenocarcinoma.
• Targeting this axis may offer a novel strategy to overcome treatment resistance in PDAC.