A study led by Ludwig Institute Scientific Director Chi Van Dang and Research Associate Xue Zhang found that the circadian clock, rather than being invariably tumor suppressive, has a contextually variable role in cancer. The researchers reported in a January paper in Nature Communications that loss of Bmal1, a master regulator of the cellular clock, dampens rather than accelerates the growth of melanoma tumors in mice because it compromises the activity of HIF1, which coordinates cellular adaptations to the hypoxic conditions. Chi, Xue and colleagues also showed that the effects of over-expressed Bmal1 on melanoma growth had nothing to do with its primary role as a regulator of gene expression. Rather, in melanoma cells ectopic Bmal1 binds and sequesters a protein involved in cell motility, MYH9, that is thought to be a tumor suppressor. The researchers detailed MYH9’s mechanism of tumor suppression and showed that Bmal1’s sequestration of MYH9 reverts melanoma cells into an immature “mesenchymal” state associated with resistance to immunotherapy. Melanoma cells expressing high levels of Bmal1 form tumors in mice that are poorly infiltrated with anti-cancer immune cells and tend to house immunosuppressive cells instead. The findings show Bmal1 drives tumor growth and immunotherapy resistance in melanoma and suggest its effect on tumorigenesis likely varies between cancer types.
Cell state dependent effects of Bmal1 on melanoma immunity and tumorigenicity
Nature Communications, 2024 January 20