Identification of molecular and functional subtypes using chronic pancreatitis patient-derived organoid models

Osorio-Vasquez, V.; Lumibao, J. C.; Peck, K. L.; Lande, K.; Zhu, J.; Stamp, M.; Okhovat, S. R.; Song, H.; Ogawa, S.; Hsu, J.; Dai, Y.; Rock, A.; Bottomley, C.; Thomas, E.; McGriff, T.; Fowler, A.; Larsen, S.; Abdulla, M.; Gibson, J.; Greer, P.; Downes, M.; Evans, R.; Zou, J.; Lowy, A.; Whitcomb, D. C.; White, R.; Bellin, M.; Tiriac, H.; Engle, D. D.

doi:10.1101/2024.10.30.620903

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bioRxiv · 10.1101/2024.10.30.620903

Identification of molecular and functional subtypes using chronic pancreatitis patient-derived organoid models

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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.

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Osorio-Vasquez, V., Lumibao, J. C., Peck, K. L., Lande, K., Zhu, J., Stamp, M., Okhovat, S. R., Song, H., Ogawa, S., Hsu, J., Dai, Y., Rock, A., Bottomley, C., Thomas, E., McGriff, T., Fowler, A., Larsen, S., Abdulla, M., Gibson, J., Greer, P., Downes, M., Evans, R., Zou, J., Lowy, A., Whitcomb, D. C., White, R., Bellin, M., Tiriac, H., Engle, D. D.. 2024-11-03. Identification of molecular and functional subtypes using chronic pancreatitis patient-derived organoid models. https://doi.org/10.1101/2024.10.30.620903

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