Abstract A079: Leveraging a human chronic pancreatitis organoid biobank for pancreatic cancer interception

Abstract

Chronic pancreatitis (CP) is a major risk factor for pancreatic ductal adenocarcinoma (PDA), yet human mechanisms that connect fibroinflammatory injury to malignant transformation remain poorly defined. We hypothesized that impaired ductal bicarbonate transport creates a reversible, transformation-permissive epithelial state that sensitizes the pancreas to oncogenic KRAS and sustains PDA. To test this, we built from a newly established human CP patient-derived organoid (PDO) platform and integrated normal pancreas, CP, and PDA PDOs with matched tissues, RNA sequencing, proteomics, immunoblotting, immunohistochemistry, forskolin-induced swelling assays, and pharmacologic rescue of cystic fibrosis transmembrane conductance regulator (CFTR)-centered transport. In the CP PDO platform, 37 organoid lines were generated from idiopathic, hereditary, alcohol-related, and other CP etiologies with 73% overall efficiency and high genetic concordance with primary tissue. CP PDOs retained epithelial-intrinsic inflammatory, fibrotic, and mitogenic programs despite removal from the native microenvironment, including elevated IL1A, IL6, TGFB2, CA19-9, and activation of STAT3/EGFR/AKT/ERK signaling. Genomic analysis also identified rare epithelial-enriched somatic alterations associated with PDA, including KRAS and TP53, in CP PDOs that were not detected in low-cellularity primary specimens. Functionally, CFTR-dependent swelling was impaired in 5/9 CP PDOs tested, including CFTR-wildtype models, indicating that ductal transport failure can arise through both genetic and non-genetic mechanisms. Treatment with the CFTR modulators restored CFTR function in responsive models and decreased inflammatory and mitogenic signaling. We next extended this framework to pancreatic cancer. Across human PDA specimens and PDOs, CFTR and the coordinated bicarbonate transport machinery, including SLC4A4 and AQP1, were frequently reduced, suggesting that malignant progression is accompanied by collapse of ductal homeostatic transport. Importantly, restoration of CFTR-centered transport was sufficient to restore functional swelling responses in transport-deficient PDA PDOs and suppress pro-oncogenic signaling nodes. Together, these data support a model in which CP-associated ductal dysfunction is not only a marker of epithelial injury, but a modifiable state that links pancreatitis to KRAS-permissive transformation and PDA maintenance. This work establishes bicarbonate transport restoration as a therapeutic interception strategy for CP and suggests utility in PDA. Generative artificial intelligence was used to assist with abstract clarity.