Multi-stromal organoid co-culture modelling reveals epithelial–fibroblast heterogeneity in pancreatic cancer and pancreatitis

Interactions between epithelial cells and fibroblasts influence disease progression and treatment response in pancreatic ductal adenocarcinoma (PDAC). While the diversity of fibroblasts in PDAC is increasingly recognized, it remains unclear how these cells differ from fibroblasts found in pancreatic inflammation. Chronic pancreatitis is a stroma-rich inflammatory disease and a risk factor for PDAC, making it a useful setting to study how epithelial cells and fibroblasts change during disease. Here we compare fibroblast diversity and epithelial–stromal interactions in pancreatitis and PDAC using human samples, mouse models and mouse pancreatitis-derived epithelial organoids. We also developed pancreatitis and PDAC organoid co-cultures containing pancreatic stellate cells, fibroblasts and mesothelial cells. Combining in vitro and in vivo models better reflected human disease than mouse models alone. Overall, our findings reveal distinct epithelial and fibroblast features in pancreatitis and PDAC and provide models to identify disease-specific markers and therapeutic vulnerabilities.