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Isolation and Characterization of Patient-derived Pancreatic Ductal Adenocarcinoma Organoid Models
Published on: January 14, 2020
Chronic pancreatitis patient-derived organoids reveal new paths to precision therapeutics
Victoria Osorio-Vasquez1, Jonathan Zhu1, Jan C Lumibao1
1Salk Institute for Biological Studies, La Jolla, CA, USA.
Abstract:
Chronic pancreatitis (CP) affects ~3 million people worldwide, yet altering the course of disease is challenging. We developed a patient-derived organoid (PDO) platform to investigate the molecular pathogenesis of this disease and identify therapeutic strategies. We generated 36 PDOs from patients with idiopathic, hereditary, and alcohol-related CP with high genetic concordance. PDOs retained inflammation-associated transcriptional and proteomic features. Transcriptomic profiling revealed three molecular subtypes of CP independent of etiology. We discovered widespread dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) in half of the CP PDOs, including those with wildtype CFTR. Clinically available CFTR modulators stabilized mutant or wildtype CFTR, restored CFTR function, and decreased mitogenic and inflammatory signaling. This work provides the first comprehensive PDO platform for modeling CP. We demonstrate the utility of this platform for precision therapeutic investigations. Our findings reveal CFTR modulators as a broadly applicable and effective therapeutic strategy.
Insights
Patient-derived organoids model chronic pancreatitis (CP) and reveal widespread cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction. CFTR modulators offer a promising therapeutic strategy for CP patients.
Area of Science:
- Gastroenterology and Hepatology
- Molecular Biology
- Translational Medicine
Background:
- Chronic pancreatitis (CP) is a debilitating disease affecting millions globally, with limited therapeutic options.
- Understanding the molecular mechanisms driving CP is crucial for developing effective treatments.
Purpose of the Study:
- To establish a patient-derived organoid (PDO) platform for modeling chronic pancreatitis (CP).
- To investigate the molecular pathogenesis of CP and identify novel therapeutic targets.
- To evaluate the efficacy of cystic fibrosis transmembrane conductance regulator (CFTR) modulators in CP.
Main Methods:
- Generation and characterization of 36 patient-derived organoids (PDOs) from diverse CP etiologies.
- Transcriptomic and proteomic profiling of PDOs to identify molecular features and subtypes.
- Functional assessment of CFTR activity and response to CFTR modulators in CP organoids.
Main Results:
- PDOs accurately recapitulated the transcriptional and proteomic hallmarks of CP, including inflammation.
- Transcriptomic analysis identified three distinct molecular subtypes of CP, irrespective of the underlying cause.
- Widespread cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction was observed in half of the CP PDOs, including those with wild-type CFTR.
- Clinically approved CFTR modulators restored CFTR function and reduced inflammatory and mitogenic signaling in CP organoids.
Conclusions:
- The developed PDO platform serves as a comprehensive model for studying CP pathogenesis.
- CFTR modulators demonstrate broad applicability and efficacy in stabilizing CFTR function and mitigating CP-associated signaling pathways.
- This research paves the way for precision therapeutic strategies targeting CFTR in chronic pancreatitis.
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