In a recent study, researchers have discovered that the circadian clock, which is responsible for synchronizing physiological and cellular activities with the day-night cycle, has a variable role in cancer development. The commonly held belief is that the circadian clock acts as a tumor suppressor. However, the study conducted by the Ludwig Institute for Cancer Research challenges this belief by revealing that the loss of a gene called Bmal1, which serves as a master regulator of the cellular clock, actually inhibits the growth of melanoma tumors in mice.
The research team, led by Chi Van Dang, scientific director of the Ludwig Institute for Cancer Research, initially anticipated that disrupting the biological clock would accelerate tumor growth in mouse models of melanoma. However, their findings proved otherwise. The study, published in Nature Communications, discovered previously unknown mechanisms that contribute to tumor suppression and resistance to immunotherapy in melanoma.
According to Xue Zhang, a research associate involved in the study, these findings could have implications for the design of chronotherapies. Chronotherapies aim to coordinate cancer treatments with biological rhythms to enhance effectiveness and reduce side effects.
The circadian clock ensures that the body’s physiology and the metabolism of each individual cell align with the solar cycle. This synchronization allows for periods of rest and recuperation, alternating with phases of vibrant activity. While healthy cells experience oscillating metabolic activity in line with the biological clock, cancer cells rewire their metabolism to sustain unrestrained growth.
Dr. Dang’s research focuses on understanding the connection between cancer cell metabolism and the malfunctioning of biological clocks. Previous studies led by Dr. Dang demonstrated that oncogenic versions of the Myc gene, which is a master regulator of cancer metabolism, suppress Bmal1 to unleash uncontrolled cell proliferation.
However, the slow growth of melanoma tumors lacking Bmal1 contradicted these previous findings. To uncover the reasons behind this contradiction, the researchers analyzed changes in gene expression in these cells. They discovered that the loss of Bmal1 compromised the activity of HIF1, another master regulator of gene expression, which allows cancer cells to adapt to low-oxygen conditions often found in solid tumors.
The research team also found that melanoma cells lacking Bmal1 could resume tumor growth when high levels of HIF1 were expressed. This indicated that Bmal1 acts as a tumor suppressor. Interestingly, a version of Bmal1 that was unable to bind to DNA, a requirement for regulating circadian gene expression, actually stimulated tumor growth.
These findings have left the research team perplexed, as the results do not align with the typical expectations. Further research is needed to fully understand the complex interactions between the circadian clock, gene expression, and tumor growth. However, this study provides valuable insights into the role of the biological clock in cancer development and has the potential to shape future therapies that align with biological rhythms.
