Chronic jetlag accelerates pancreatic neoplasia in conditional Kras-mutant mice

ABSTRACT

Misalignment of the circadian clock compared to environmental cues causes circadian desynchrony, which is pervasive in humans. Clock misalignment can lead to various pathologies including obesity and diabetes, both of which are associated with pancreatic ductal adenocarcinoma – a devastating cancer with an 80% five-year mortality rate. Although circadian desynchrony is associated with an increased risk of several solid-organ cancers, the correlation between clock misalignment and pancreas cancer is unclear. Using a chronic jetlag model, we investigated the impact of clock misalignment on pancreas cancer initiation in mice harboring a pancreas-specific activated Kras mutation. We found that chronic jetlag accelerated the development of pancreatic cancer precursor lesions, with a concomitant increase in precursor lesion grade. Cell-autonomous knock-out of the clock in pancreatic epithelial cells of Kras-mutant mice demonstrated no acceleration of precursor lesion formation, indicating non-cell-autonomous clock dysfunction was responsible for the expedited tumor development. Therefore, we applied single-cell RNA sequencing over time and identified fibroblasts as the cell population manifesting the greatest clock-dependent changes, with enrichment of specific cancer-associated fibroblast pathways due to circadian misalignment.

KEYWORDS:

• Circadian
• pancreas
• jetlag
• pancreatic ductal adenocarcinoma
• misalignment

Acknowledgments

We would like to take the opportunity to acknowledge the University of Wisconsin Carbone Cancer Center Support Grant P30 CA014520, which provides funding for the Experimental Animal Pathology Lab Core.

The author(s) thank the University of Wisconsin Translational Research Initiatives in Pathology laboratory (TRIP), supported by the UW Department of Pathology and Laboratory Medicine, UWCCC (P30 CA014520) and the Office of The Director- NIH (S10 OD023526) for use of its facilities and services.

We would also to acknowledge the Gene Expression Center and the Bioinformatics Resource Center (BRC) at the University of Wisconsin, Madison for their contributions to this work.

Finally, we would like to thank the Michael W. Oglesby Foundation for their funding support of our work in circadian disruption and pancreas pathology.

Disclosure statement

No potential conflict of interest was reported by the authors.

Data statement

Single-cell RNA sequencing data is made publicly available through gene expression omnibus (GEO) (Accession number: GSE209629). All other data that support the findings of this study are available from the corresponding author, SRK, upon reasonable request.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/07420528.2023.2186122

Additional information

Funding

The research reported in this publication was supported by the Department of Defense Peer Reviewed Cancer Research Program Award CA190176 (Grants.gov ID GRANT12935023) and the University of Wisconsin Institute for Clinical and Translational Research KL2 Award (UL1TR002373 and KL2TR002374) [SRK]. Funding support for this work was also provided by the National Institutes of Health under Award Number T32 ES007015 [PBS]. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.