Abstract
Disruption of the circadian clock is inextricably linked to cancer development and progression. Establishing this connection has proven beneficial for understanding cancer pathogenesis, determining prognosis, and uncovering novel therapeutic targets. However, barriers to characterizing the circadian clock in human pancreas and human pancreatic cancer – one of the deadliest malignancies – have hindered an appreciation of its role in this cancer. Here, we employed normalized coefficient of variation (nCV) and clock correlation analysis in human population-level data to determine the functioning of the circadian clock in pancreas cancer and adjacent normal tissue. We found a substantially attenuated clock in the pancreatic cancer tissue. Then we exploited our existing mouse pancreatic transcriptome data to perform an analysis of the human normal and pancreas cancer samples using a machine learning method, cyclic ordering by periodic structure (CYCLOPS). Through CYCLOPS ordering, we confirmed the nCV and clock correlation findings of an intact circadian clock in normal pancreas with robust cycling of several core clock genes. However, in pancreas cancer, there was a loss of rhythmicity of many core clock genes with an inability to effectively order the cancer samples, providing substantive evidence of a dysregulated clock. The implications of clock disruption were further assessed with a Bmal1 knockout pancreas cancer model, which revealed that an arrhythmic clock caused accelerated cancer growth and earlier metastatic spread, accompanied by chemoresistance and enrichment of key cancer-related pathways. These findings provide strong evidence for clock disruption in human pancreas cancer and demonstrate a link between circadian disruption and pancreas cancer progression.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
Funding: The research reported in this publication was supported by the Department of Defense Peer Reviewed Cancer Research Program Idea Award Number CA190176 (Grants.gov ID GRANT12935023) (SRK), by the National Institutes of Health (NIH) National Institute of Environmental Health Sciences (NIEHS) Award Number R35ES028377 (CAB), by the NIH NIEHS Award Number T32 ES007015 (PBS) and the University of Wisconsin Carbone Cancer Center (SRK). The content is solely the responsibility of the authors and does not necessarily represent the official views of the Department of Defense or the National Institutes of Health.
Disclosure: The authors declare no conflict of interest or competing interests
Updated missing methodologic details.