The Surprising Relevance of Circadian Disruption

La Jolla, California—Disturbances in circadian rhythms (how our bodies respond to 24-hour light-dark cycles) are associated with a variety of diseases, including cancer. Even though shift workers and others with irregular schedules regularly experience these disruptions, the relationship between the two is poorly understood. But new findings from Scripps Research help shed light on what’s behind this correlation.

was announced in scientific progress The September 28, 2022 findings highlight that chronic circadian rhythm disruption significantly increased lung cancer growth in animal models. By identifying the genes involved, researchers are unraveling the mysterious link between sleep patterns and disease. This could help inform everything from developing more targeted cancer treatments to better monitoring of high-risk groups.

“There has always been a lot of evidence that shift workers and people with disrupted sleep schedules have higher rates of cancer. Our mission in this study was to find out why,” said the senior author. said Dr. Katya Lamia of of molecular medicine.

To answer this question, scientists used a mouse model expressing KRAS, the most commonly mutated gene in lung cancer. Half of the mice were housed on a ‘normal’ light cycle, meaning 12 hours light and 12 hours darkness. The other half was housed in a light cycle that advanced his light hours by 8 hours every few days, simulating a shift worker’s light cycle.

This finding matched what the researchers originally thought. That is, mice exposed to irregular and changing light patterns had a 68% increase in tumor burden.

However, when we used RNA sequencing to identify different genes involved in cancer growth, we were surprised to find that a collection of proteins in the heat shock factor 1 (HSF1) family were the main culprits.

“This is not the mechanism we expected here. HSF1 has been shown to increase tumorigenicity in several different cancer models, but has been previously associated with circadian rhythm disruption.” I had never seen it before,” says Lamia.

The HSF1 gene is responsible for ensuring that the protein is made correctly even when the cell is under extreme stress, in this case when it experiences temperature changes. The team suspects that he increases HSF1 activity in response to disruptions in circadian rhythms because changes in sleep cycles disrupt the daily rhythm of body temperature.

“Normally, our body temperature changes by a degree or two while we sleep. It can lead to dysregulation in the body,” adds Lamia. She suspects that cancer cells could exploit her HSF1 pathway for their own benefit, creating mutated, misfolded proteins, but more research is needed in this area. she says there is.

These findings not only advance our understanding of how circadian rhythms affect cancer, but may also help preventative measures to protect more vulnerable groups at risk. . By noninvasively monitoring body temperature, it may be possible to optimize shift worker schedules and even stop this kind of dysregulation that leads to cancer.

With these findings in hand, scientists are now assessing whether HSF1 signaling is required to increase tumor burden and not just a correlation.

“Now that we know there is a molecular link between HSF1, circadian rhythm disruption, and tumor growth, it’s our job to determine how they all relate,” says Lamia. says.

In addition to Lamia, authors of the study “Circadian Disruption Promotes HSF1 Signaling and Tumorigenesis in Kras-Driven Lung Cancer” include Marie Pariollaud, Lara H. Ibrahim, Emanuel Irizarry, Rebecca M. Mello, Alanna B. Chan, Michael J. Bollong and R. Luke Wiseman of Scripps Research. Brian J. Altman, University of Rochester Medical Center. and Reuben J. Shaw of the Salk Institute.

This study was funded by National Institutes of Health grant CA211187 (KAL), Brown Cancer Research Foundation (KAL), National Institutes of Health grant DK107604 (RLW), and National Institutes of Health grant R00CA204593 (BJA). , and provided by the National Science Foundation. /DBI-1759544 (EI).

About Scripps Research

Scripps Research is an independent, not-for-profit biomedical research institute, ranked as the world’s most influential force for innovation by the Nature Index. We improve human health through key discoveries that address pressing medical concerns around the world. Calibr, our drug discovery and development arm, collaborates with scientists from many disciplines to bring new medicines to patients as quickly and efficiently as possible. Meanwhile, the Scripps Research Translational Institute team is leveraging genomics, digital medicine, and cutting-edge informatics to understand individual health and deliver more effective care. Scripps Research is also training the next generation of leading scientists at the Skaggs Graduate School, consistently named among the top 10 chemical and biological science programs in the United States.Click here for details www.scripts.edu.