The Circadian Clock is Disrupted in Pancreatic Cancer

Patrick B. Schwartz, Manabu Nukaya, Mark E. Berres, Clifford D. Rubinstein, Gang Wu, John B. Hogenesch, Christopher A. Bradfield, Sean M. Ronnekleiv-Kelly.

Abstract

Disruption of the circadian clock is 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.

Introduction

The circadian clock is a conserved molecular feedback loop that regulates many signaling pathways to control metabolism, immunity, apoptosis, and other critical cellular functions in the body. At its core, the positive arm of the clock (i.e., CLOCK and BMAL1 [also known as ARNTL or MOP3]) drives transcription of the negative arm, including PER1-3 and CRY1-2.

Material and Methods:

Ethics statement

All animal studies were conducted according to an approved protocol (M005959) by the University of Wisconsin School of Medicine and Public Health (UW SMPH) Institutional Animal Care and Use Committee (IACUC). This committee and approval ensures all animal studies were conducted by internationally-accepted standards.

Discussion

Our work herein used matched normal and tumor samples from TCGA and CPTAC-3 to provide the first substantive evidence, to our knowledge, that the circadian clock is disrupted in PDAC while the adjacent normal pancreatic clock is intact. Recently published work by Talamanca et al. also demonstrated an intact circadian clock in human pancreas, albeit pancreas from human donors and not tumor-adjacent pancreas.

Acknowledgments:

We would like to acknowledge the Gene Expression Center and the Bioinformatics Resource Center (BRC) at the University of Wisconsin, Madison for their contributions to this work. The authors thank the University of Wisconsin Carbone Cancer Center Flow Cytometry Laboratory, supported by P30 CA014520, for use of its facilities and services.

Citation: Schwartz PB, Nukaya M, Berres ME, Rubinstein CD, Wu G, Hogenesch JB, et al. (2023) The circadian clock is disrupted in pancreatic cancer. PLoS Genet 19(6): e1010770. https://doi.org/10.1371/journal.pgen.1010770

Editor: Robert Dallmann, University of Warwick, UNITED KINGDOM

Received: November 23, 2022; Accepted: May 1, 2023; Published: June 1, 2023.

Copyright: © 2023 Schwartz et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: The TCGA and CPTAC-3 data were requested from the following URL: https://portal.gdc.cancer.gov/. All RNAseq data can be found on the Gene Expression Omnibus (GEO) at accession numbers GSE213680 and GSE165198. The modified KPC cell lines (KPC-BKO and KPC Per2-dLuc) created for use in this manuscript are available through Material Transfer Agreement by contacting Vasanthi Pillai at the University of Wisconsin Research and Sponsored Programs (contracts@rsp.wisc.edu). All of the numerical data to generate the figures and statistics for this manuscript are included in S4 Data.

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) (SMRK), 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), the University of Wisconsin Carbone Cancer Center Support Grant P30CA014520 (SMRK) and by the Michael W. Oglesby Foundation (SMRK). 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. The funding agencies did not play any role in the study design, data collection and analysis, decision to publish or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.