Chronic Jetlag Accelerates Pancreatic Neoplasia in Conditional Kras-Mutant Mice

Pancreatic ductal adenocarcinoma (PDAC) is a devastating cancer with an 80% five-year mortality rate - reflecting an inadequate understanding of pertinent drivers of cancer development. One potential driver of PDAC development is circadian disruption, known to control a myriad of pancreatic processes. Clock dysfunction is associated with multiple risk factors for PDAC, including obesity, diabetes, and heightened inflammation, and has been shown to accelerate the development of other solid-organ cancers. Using a well-characterized model of chronic jetlag (CJ) to mimic irregular sleep patterns, we subjected mice harboring a pancreas-specific activated Kras mutation (KC mice) to either a normal lighting pattern or CJ and observed the resultant histopathologic changes. We found that CJ accelerated the development of fibroinflammatory infiltrate/pancreatic intraepithelial neoplasia and increased the grade of the pancreatic lesions. Applying single-cell RNA sequencing over multiple time points, we further identified fibroblasts in the developing pancreatic tumor microenvironment as a putative target of CJ-induced changes. Our results suggest a role for clock dysfunction in PDAC initiation which may hold relevance for preventative efforts. ### Competing Interest Statement The authors have declared no competing interest.