Beta cells are essential drivers of pancreatic ductal adenocarcinoma development
Garcia, C. C.; Venkat, A.; McQuaid, D. C.; Agabiti, S. S.; Tong, A.; Cardone, R. L.; Starble, R.; Sogunro, A.; Jacox, J. B.; Ruiz, C. F.; Kibbey, R.; Krishnaswamy, S.; Muzumdar, M. D.
Show abstract
Pancreatic endocrine-exocrine crosstalk plays a key role in normal physiology and disease. For instance, endocrine islet beta ({beta}) 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 {beta} cell ablation impedes PDAC development in mice, arguing that the endocrine pancreas is critical for exocrine tumorigenesis. Conversely, obesity induces {beta} 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 {beta} 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.
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