Studying circadian clock disruption to explore new pancreas cancer treatment

This natural biological process optimizes a wide range of bodily functions to ramp up or slow down based on the consistent 24-hour time frame of light and dark in a day. Disruptions to circadian rhythm, such as jet lag, eating big meals later in the day and prolonged exposure to light, can have multiple health impacts even after you feel back to normal.

That’s because those ebbs and peaks in activity occur in organ systems and even at the cellular level.

“The whole function of the circadian clock is to optimize the timing of internal systems with respect to the external environment, which provides metabolic advantage; you’re not wasting a lot of metabolic energy,” said Dr. Sean Ronnekleiv-Kelly, a surgical oncologist and researcher for the UW Carbone Cancer Center and UW Department of Surgery. “We as humans now no longer adhere to that, not even close. So there is this concept of social jet lag, or circadian misalignment, where our internal clock is trying to function according to biology, but the external cues are misaligning with that.”

Those cellular disruptions have implications for development and progression of multiple types of cancer, but it had been relatively unexplored for pancreas cancer. Ronnekleiv-Kelly hopes that establishing the mechanism at play can lead to new treatment options for one of the deadliest types of cancer.

“Pancreas cancer has always been a focus for me because of how devastating it is,” Ronnekleiv-Kelly said. “Despite long duration chemotherapy, operations or radiation, the outcome for these patients is pretty poor.”

Ronnekleiv-Kelly’s team began by establishing that chronic jetlag (circadian misalignment) in mice affected the timing of peak core clock and clock-associated gene expression in the pancreas. It also took several days after returning the mice to normal light conditions for the pancreas circadian clock to return to normal function.

“We built upon that research to look at the effect of chronic jet lag in pancreas cancer development, and we actually found that it accelerates the pancreas cancer pre-neoplastic formation, which was interesting but also alarming to see,” Ronnekleiv-Kelly said.

His team then turned to large-scale data analysis on circadian clock function in healthy and malignant human pancreas tissue, showing the clock was intact in healthy tissue but disrupted in cancerous samples.

“The reason why this is important, is when you look at other cancers where the clock is disrupted within the cancer tissue, it tends to portend a worse prognosis and more aggressive cancer phenotype, and it can also be targeted for a novel therapeutic effect,” he said. “So that study was critical because it really laid the foundation of the fact that there is strong evidence that the clock is disrupted in pancreas cancer at a population level.”

Their next phase of work is evaluating those impacts at an individual patient level. It’s crucial to thoroughly explore the cause and effect of clock disruption on cancer progression to explore possible targeted therapies.

“The ultimate idea in pancreas cancer is that if we can start to identify which patients have a disrupted clock within their cancer tissue, and what kind of mechanistic downstream sequela there is as a result of the disrupted clock … then the idea would be you can target the modification or the change and similarly suppress whatever metabolic advantage is occurring,” he said.