Galectin-1 drives pancreatic carcinogenesis through stroma remodeling and Hedgehog signaling activation

Area of Science:

• Oncology
• Cancer Biology
• Tumor Microenvironment

Background:

• Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer with limited treatment options.
• The desmoplastic stroma in PDAC contributes significantly to therapeutic resistance.
• Galectin-1 (Gal1), a glycan-binding protein, is highly expressed in PDAC stroma but its role is uncharacterized.

Purpose of the Study:

• To investigate the functions and molecular pathways of galectin-1 (Gal1) in pancreatic ductal adenocarcinoma (PDAC).
• To determine if Gal1 contributes to oncogenic properties within the PDAC tumor microenvironment.
• To evaluate Gal1 as a potential therapeutic target for PDAC.

Main Methods:

• Genetic ablation of Gal1 in a mouse model of PDAC (EIa-myc mice).
• In vitro and in vivo cellular analyses.
• Investigation of molecular pathways, including Hedgehog signaling.

Main Results:

• Genetic ablation of Gal1 inhibited PDAC progression, including proliferation, angiogenesis, and desmoplasia.
• Gal1 ablation stimulated a tumor-associated immune response, increasing lifespan by 20%.
• Gal1 regulates acinar-to-ductal metaplasia and promotes Hedgehog pathway signaling in PDAC cells and stromal fibroblasts.

Conclusions:

• Galectin-1 plays a critical role in tumor-stroma crosstalk within pancreatic ductal adenocarcinoma.
• Targeting Gal1 represents a viable microenvironment-based therapeutic strategy for PDAC.
• These findings provide a preclinical rationale for developing Gal1-targeted therapies for pancreatic cancer.