Patient-derived organoids of pancreatic ductal adenocarcinoma for subtype determination and clinical outcome...

Area of Science:

• Oncology
• Gastroenterology
• Molecular Biology

Background:

• Pancreatic ductal adenocarcinoma (PDAC) has two proposed molecular subtypes: Classical and Basal-like.
• The Classical subtype is associated with better clinical outcomes compared to the Basal-like subtype.
• Current molecular classification is not widely used in clinical practice.

Purpose of the Study:

• To establish patient-derived organoids (PDOs) for PDAC.
• To evaluate PDOs for classifying PDAC subtypes.
• To assess the predictive value of PDOs for clinical outcomes and treatment response.

Main Methods:

• Tumor samples were obtained via endoscopic ultrasound-guided fine-needle biopsy.
• A library of PDOs was established for morphological assessment, RNA-seq, and drug response assays.
• A prospective clinical study was conducted to validate PDO-based predictions.

Main Results:

• High efficiency (> 70%) in establishing PDAC PDOs with over 100,000 live cells.
• Morphological classification of PDOs (gland-like vs. densely proliferating) correlated with molecular subtypes (Classical vs. Basal-like).
• Morphological subtype predicted clinical outcomes, with gland-like structures showing significantly longer overall survival (P < 0.005).
• Gland-like PDOs responded better to gemcitabine; densely proliferating PDOs showed improved response with ERK inhibitor and chloroquine combination.

Conclusions:

• PDAC PDOs enable accurate subtype determination.
• PDOs serve as a valuable tool for predicting clinical outcomes in PDAC patients.
• This organoid model facilitates bench-to-bedside precision medicine for PDAC.