Summary: New research links disruption of the circadian clock to increased tumor growth.
Source: MIT.
Study reveals connection between circadian clock disruption and tumor progression
Several large studies have reported that working night shifts—which nearly 15 percent of Americans do—increases the risk of developing cancer. Researchers at MIT now provide experimental evidence that helps explain this association.
Across species, the circadian clock, driven primarily by light exposure, coordinates the timing of many physiological processes, including cellular metabolism and division. In a study using genetically engineered mice prone to non-small cell lung cancer, MIT scientists found that two core circadian genes also act as tumor suppressors: Bmal1 and Per2. Disrupting these genes, either genetically or by disturbing normal light/dark cycles, promoted faster, more aggressive tumor growth.
“Whether you disturb the clock through genetic loss or by altering environmental light cues, the result appears to be the same: increased tumorigenesis,” says Thales Papagiannakopoulos, the study’s lead author and a former postdoctoral researcher at MIT’s Koch Institute for Integrative Cancer Research. The work is reported in the July 28 issue of Cell Metabolism. Tyler Jacks, director of the Koch Institute, is senior author.
How the circadian clock is broken
In mammals, the master circadian clock resides in the brain’s suprachiasmatic nucleus (SCN), which receives light information from the retina and relays timing signals to the rest of the body via hormones and molecular messengers. At the cellular level, the transcription factor Bmal1 activates other clock genes, including Per2, producing proteins that oscillate over a 24-hour cycle. When normal light/dark cycles are disrupted, those oscillations are lost and cells no longer maintain synchronized daily rhythms.
“Light acts as a daily reset for the clock. Remove or scramble that cue and cells lose their normal rhythms,” Papagiannakopoulos explains. To test whether these disruptions contribute to cancer progression, the team used mice that develop lung adenocarcinoma and subjected them to different light schedules.
One group experienced a standard 12-hour light / 12-hour dark cycle. A second group underwent a repeated “jet lag” schedule: every two to three days they received an extra eight hours of light, simulating the circadian disruption caused by shift work or frequent long-distance travel. Tumors in the jet-lagged mice grew faster and were more aggressive than those in mice kept on a normal light/dark schedule.
In complementary experiments, researchers left the light/dark cycle unchanged but genetically deleted Bmal1 or Per2 in the mice. Those animals developed tumors that also grew more rapidly and progressed more aggressively, mirroring the effect of the jet-lag condition. “Genetic loss of these core clock components is like taking a molecular hammer to the clock,” Papagiannakopoulos says.
Uncontrolled growth driven by metabolic changes
Bmal1 and Per2 regulate the timing of many cellular programs, including the production of the oncogene c-Myc. Loss of these circadian regulators led to elevated c-Myc levels, which in turn triggered increased cellular metabolism and proliferation. “C-Myc drives a program that boosts production of metabolites and building blocks needed for cell growth,” Papagiannakopoulos notes, “so when clock control is lost, cells shift into a pro-growth, pro-proliferation state.”
Joseph Takahashi, chair of the Department of Neuroscience at the University of Texas Southwestern Medical Center and an expert in circadian biology, described the study as a clear demonstration that circadian dysfunction can influence cancer progression. “This work is rigorous and helps establish a mechanistic link between clock disruption and tumor biology,” he commented.
To extend their findings to humans, the MIT team analyzed human lung tumor samples and observed markedly reduced expression of Bmal1, Per2, and other circadian genes in tumors compared with adjacent normal lung tissue. Tumors with the lowest levels of these clock genes were the most aggressive, supporting the experimental results from mice.
Papagiannakopoulos is pursuing follow-up studies to determine whether cancers that lose circadian function develop specific vulnerabilities that could be targeted therapeutically. He also plans to investigate how circadian disruption affects other cancer types, including pancreatic cancer.
Funding: The research was supported by a National Cancer Institute Cancer Center Support Core Grant, the Lung Cancer Research Foundation, and the Koch Institute Frontier Fund.
Source: Anne Trafton, MIT.
Image credit: National Cancer Institute, Christine Daniloff/MIT.
Original research: Abstract for “Circadian Rhythm Disruption Promotes Lung Tumorigenesis” by Thales Papagiannakopoulos, Matthew R. Bauer, Shawn M. Davidson, Megan Heimann, Lakshmipriya Subbaraj, Arjun Bhutkar, Jordan Bartlebaugh, Matthew G. Vander Heiden, and Tyler Jacks, published in Cell Metabolism on July 28, 2016. DOI: 10.1016/j.cmet.2016.07.001.
MLA: MIT. “Why Working the Night Shift Can Pose a Cancer Risk.” NeuroscienceNews. 29 July 2016.
APA: MIT. (2016, July 29). Why Working the Night Shift Can Pose a Cancer Risk. NeuroscienceNews. Retrieved July 29, 2016.
Chicago: MIT. “Why Working the Night Shift Can Pose a Cancer Risk.” NeuroscienceNews. Accessed July 29, 2016.
Abstract
Circadian Rhythm Disruption Promotes Lung Tumorigenesis
Highlights
• Physiologic disruption of circadian rhythms accelerates lung cancer progression
• Genetic loss of Per2 or Bmal1 promotes lung tumorigenesis
• Cell-autonomous loss of circadian genes enhances transformation and tumor growth
• Circadian disruption increases c-Myc levels and produces metabolic reprogramming
Summary
Circadian rhythms are endogenous 24-hour oscillations that regulate many biological processes, including cell division and metabolism—two hallmarks of cancer. Epidemiologic data link shift work and circadian disruption to higher cancer risk and worse prognosis, suggesting that intact circadian rhythms may play a tumor-suppressive role. Using a genetically engineered mouse model of lung adenocarcinoma, this study examined the effects of both environmental perturbation (repeated jet lag) and genetic disruption of central clock components. Both types of disruption decreased survival and promoted tumor growth and progression. The core clock genes Per2 and Bmal1 act in a cell-autonomous manner to suppress transformation and tumor progression. Loss of these components elevates c-Myc expression, enhances proliferation, and alters metabolic regulation. These findings indicate that both systemic and somatic circadian disruption can contribute to cancer progression.
“Circadian Rhythm Disruption Promotes Lung Tumorigenesis” by Thales Papagiannakopoulos et al., Cell Metabolism, published online July 28, 2016. DOI: 10.1016/j.cmet.2016.07.001