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Abstract For a long time, the pancreas was thought to have separate cellular compartments that functioned distinctly from one another. The endocrine pancreas (islets of Langerhans) regulates glucose homeostasis, while the exocrine pancreas (acini and ducts) produces and secretes digestive enzymes. However, it has recently become clear that the endocrine and exocrine compartments communicate with one another, and dysfunction in one leads to dysfunction in the other, resulting in diabetes or pancreatitis. However, whether and how the endocrine pancreas drives the development of pancreatic ductal adenocarcinoma (PDAC), an exocrine tumor, remains unresolved. Strikingly, we found that genetic ablation of insulin-producing islet beta (β) cells (Akita) in a faithful Kras/Trp53-driven PDAC model (KPC: Kras LSL-G12D /+; Trp 53172 /+; Pdx1-Cre) suppressed PDAC progression. Conversely, obesity-induced β cell hormone dysregulation promoted Kras-driven PDAC development. Single-cell RNA sequencing (scRNA-seq) analysis of wild-type and obese mice (high-fat diet-fed and leptin-deficient (Lep ob/ob) ) revealed increased expression of the peptide hormone cholecystokinin (CCK) in a subset of β cells concordant with increasing obesity, and transgenic β cell overexpression of CCK was sufficient to promote exocrine tumorigenesis in KC mice. Combined in silico (pseudotime (TrajectoryNET) and archetypal (AANet) analysis) and experimental (CreER) lineage tracing demonstrated that CCK-expressing β cells originated from a pre-existing immature β cell population (virgin β cells). Grainger causality analysis of transcriptional networks uncovered a stress-induced JNK-cJun pathway that promotes CCK expression β cells, which we confirmed using JNK inhibitors in β cell models. Together, our findings identify cellular and molecular mechanisms of β cell adaptation to obesity that contribute to obesity-driven pancreatic cancer. Furthermore, we define a critical role for endocrine-exocrine signaling in PDAC progression and stress-induced β cell pathways which could be leveraged to target the endocrine pancreas to subvert exocrine tumorigenesis. Citation Format: Cathy Garcia, Aarthi Venkat, Daniel McQuaid, Sherry Agabiti, Alex Tong, Rebecca Cardone, Richard Kibbey, Smita Krishnaswamy, Mandar Muzumdar. Endocrine beta-cell stress promotes pancreatic ductal adenocarcinoma through endocrine-exocrine cell crosstalk abstract. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84 (17 Suppl₂): Abstract nr PR-05.
Garcia et al. (Sun,) studied this question.