Beta cells are essential drivers of pancreatic ductal adenocarcinoma development.

Pancreatic endocrine-exocrine crosstalk plays a key role in normal physiology and disease. For instance, endocrine islet beta (β) cell secretion of insulin or cholecystokinin (CCK) promotes progression of pancreatic adenocarcinoma (PDAC), an exocrine cell-derived tumor. However, the cellular and molecular mechanisms that govern endocrine-exocrine signaling in tumorigenesis remain incompletely understood. We find that β cell ablation impedes PDAC development in mice, arguing that the endocrine pancreas is critical for exocrine tumorigenesis. Conversely, obesity induces β cell hormone dysregulation, alters CCK-dependent peri-islet exocrine cell transcriptional states, and enhances islet proximal tumor formation. Single-cell RNA-sequencing, in silico latent-space archetypal and trajectory analysis, and genetic lineage tracing in vivo reveal that obesity stimulates postnatal immature β cell expansion and adaptation towards a pro-tumorigenic CCK+ state via JNK/cJun stress-responsive signaling. These results define endocrine-exocrine signaling as a driver of PDAC development and uncover new avenues to target the endocrine pancreas to subvert exocrine tumorigenesis.