Beta cell-derived cholecystokinin drives obesity-associated pancreatic adenocarcinoma development [CUT&RUN]
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: Min6 cells were plated (2.5 million) and grown for 3 days prior to treatment with the JNK inhibitor SP600125 (20 uM, Med Chem Express) or DMSO (control) for 48 hours. 550,000 cells were harvested per reaction and condition. Cells were processed using the CUTANA ChIC/CUT&RUN Kit (14-1048), JUN/cJun CUTANA CUT&RUN antibody (SKU:13-2019), and positive (anti-H3K4Me3) and negative (IgG) control antibodies from the kit following the manufacturer's protocol. Library preparation was performed by the Yale Center for Genome Analysis followed by sequencing to a depth of 30 million paired-end 150 bp reads (2x150) per sample on NovaSeq (Illumina).