Beta cell-derived cholecystokinin drives obesity-associated pancreatic adenocarcinoma development
Pancreatic endocrine-exocrine crosstalk plays a key role in normal physiology and disease and can be altered by host metabolic states, such as obesity. Classically, endocrine islet beta (ß) cell secretion of insulin is thought to promote the development of obesity-associated pancreatic adenocarcinoma (PDAC), an exocrine cell-derived tumor. Here, we show that ß cell expression of the peptide hormone cholecystokinin (CCK) is necessary and sufficient for obesity-associated PDAC progression in mice and that CCK expression – rather than insulin – correlates strongly with enhanced tumorigenesis. Single-cell RNA-sequencing, in silico latent-space archetypal and trajectory analysis, and experimental lineage tracing in vivo reveal that obesity induces the expansion of postnatal immature ß cells, which adapt to express CCK via stress-responsive JNK/cJun signaling. Finally, obesity perturbs CCK-dependent peri-islet exocrine cell transcriptional states and enhances islet-proximal tumor formation. These results define endocrine-exocrine CCK signaling as a bona fide driver of obesity-associated PDAC development and uncover new avenues to target the endocrine pancreas to subvert exocrine tumorigenesis. Overall design: RNA-seq profiling of pancreata isolated from 12-week old C57BL6/J mice with lean wild-type (WT) mice, obese leptin-deficient (Lep(ob/ob), aka OB) mice, or leptin-deficient (OB) mice treated 6 weeks with CCK-receptor antagonists (CCKR-I, proglumide or lorglumide) drinking water (versus control water), beginning at 6 weeks of age. All mice on standard ad libitum chow diet.