Chronic pancreatitis patient-derived organoids reveal new paths to precision therapeutics

bioRxiv. 2025 Nov 14:2024.10.30.620903. doi: 10.1101/2024.10.30.620903.

Victoria Osorio-Vasquez ¹, Jonathan Zhu ¹, Jan C Lumibao ¹, Kathryn Lande ¹ ², Kristina L Peck ¹, McKenna K Stamp ¹, Shira R Okhovat ¹, Hyemin Song ¹ ³, Satoshi Ogawa ¹, Casie Kubota ¹, Vasiliki Pantazopoulou ¹, Yang Dai ¹, Angelica Rock ¹, Chelsea Bottomley ¹, Ethan Thomas ¹, Jasper Hsu ¹ ³, Araceli Herrera Morales ¹, Alexandra Fowler ¹, T'Onj McGriff ¹, K Garrett Evensen ¹, Siri Larsen ⁴, Muhamad Abdulla ⁴, Phil Greer ⁵, Jessica Gibson ⁵, Michael Downes ¹, Ronald Evans ¹, Andrew M Lowy ⁶, David C Whitcomb ⁵ ⁷, Jingjing Zou ⁸, Alfredo Molinolo ⁹, Tae Gyu Oh ¹⁰, Rebekah White ⁶, Melena Bellin ⁴ ¹¹, Herve Tiriac ⁶, Dannielle D Engle ¹ ³

Affiliations

1 Salk Institute for Biological Studies, La Jolla, CA, USA.
2 Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
3 School of Biological Sciences Department of Molecular Biology, University of California San Diego, School of Medicine, La Jolla, CA, USA.
4 Schulze Diabetes Institute, Department of Surgery, University of Minnesota Medical School, Minneapolis, MN, USA.
5 Ariel Precision Medicine, Pittsburgh, PA, USA.
6 Department of Surgery, Division of Surgical Oncology, Moores Cancer Center, University of California San Diego, San Diego, CA, USA.
7 University of Pittsburgh, Pittsburgh, PA, USA.
8 Herbert Wertheim School of Public Health and Human Longevity Science, University of California San Diego, CA, USA.
9 Department of Pathology, Biorepository and Tissue Technology Shared Resource, Moores Cancer Center, UC San Diego, San Diego, CA, USA.
10 University of Oklahoma, College of Medicine, Oklahoma City, OK, USA.
11 Departments of Pediatrics, Division of Pediatric Endocrinology, University of Minnesota Medical School Minneapolis, MN, USA.

PMID: 41279927 DOI: 10.1101/2024.10.30.620903

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.

Keywords

CFTR; CFTR correctors; CFTR potentiators; chronic pancreatitis; molecular subtypes; patient derived organoids.

Products

Cat. No.

Product Name

Description

Target

Research Area
HY-13017

Ivacaftor

99.97%, CFTR Potentiator

CFTR; Autophagy

Endocrinology
HY-111772

Elexacaftor

99.26%, CFTR Corrector

CFTR; Autophagy

Inflammation/Immunology

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