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Updated: Jun 9, 2025
Isolation and Characterization of Patient-derived Pancreatic Ductal Adenocarcinoma Organoid Models
Published on: January 14, 2020
Tumor organoids improve mutation detection of pancreatic ductal adenocarcinoma
Elham Aida Farshadi1, Wenya Wang2, Farzana Mohammad1
1Department of Pulmonary Medicine, Erasmus University Medical Center, PO Box 2040, Rotterdam, 3000 CA, The Netherlands.
Abstract:
Pancreatic ductal adenocarcinoma (PDAC) presents challenges in detecting somatic mutations due to its complex cellular composition. This study investigated the utility of patient-derived organoids (PDOs) to overcome these obstacles and enhance somatic mutation identification. Surgically resected PDAC tumors and their paired PDOs from 21 patients were examined. Whole-exome sequencing (WES) of tumor tissue, organoids, and peripheral blood mononuclear cells was performed to identify somatic mutations. Our findings demonstrate that PDOs retained about 80% of the somatic mutations from the original tumors, showing high concordance in mutation types. PDOs exhibited increased tumor purity and uncovered key driver mutations, aiding in identifying clinically relevant genomic alterations. Moreover, eight cycles of FOLFIRINOX treatment did not significantly alter the mutational landscape at the DNA level, indicating the stability of the mutational profile after therapeutic pressure in patients. In conclusion, PDOs are potentially important tools for exploring the somatic mutational landscape of PDAC. While they can reveal mutations that may be challenging to detect through traditional biopsy sequencing due to the inherently low tumor purity of PDAC, it is important to note that PDOs may not always fully recapitulate all mutations found in primary tumors. Despite this limitation, PDOs can still offer critical insights into the genomic complexities of PDAC, which is crucial for the development of personalized vaccines and therapies for this disease.
Insights
Patient-derived organoids (PDOs) effectively capture most somatic mutations in pancreatic ductal adenocarcinoma (PDAC). These models enhance tumor purity, aiding the identification of critical mutations for personalized cancer therapies.
Area of Science:
- Oncology
- Genomics
- Cancer Biology
Background:
- Pancreatic ductal adenocarcinoma (PDAC) is characterized by complex cellularity, complicating somatic mutation detection.
- Accurate identification of somatic mutations is crucial for understanding PDAC pathogenesis and developing targeted therapies.
Purpose of the Study:
- To evaluate the utility of patient-derived organoids (PDOs) in overcoming challenges associated with somatic mutation detection in PDAC.
- To assess the concordance of somatic mutations between primary PDAC tumors and their corresponding PDOs.
Main Methods:
- Whole-exome sequencing (WES) was performed on tumor tissue, PDOs, and peripheral blood mononuclear cells from 21 PDAC patients.
- Comparative analysis of somatic mutations identified in primary tumors versus PDOs.
- Assessment of mutational landscape stability following FOLFIRINOX treatment in PDOs.
Main Results:
- PDOs retained approximately 80% of somatic mutations from the original PDAC tumors, with high concordance in mutation types.
- PDOs demonstrated increased tumor purity, facilitating the discovery of key driver mutations and clinically relevant genomic alterations.
- FOLFIRINOX treatment over eight cycles did not significantly alter the DNA-level mutational landscape of the PDOs.
Conclusions:
- PDOs serve as valuable tools for investigating the somatic mutational landscape of PDAC, particularly for mutations obscured by low tumor purity in biopsies.
- While not a perfect replica, PDOs provide critical insights into PDAC genomic complexity, supporting the development of personalized vaccines and treatments.
- PDOs can aid in identifying actionable mutations that are challenging to detect via traditional sequencing methods.
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