Circadian system ageing in cancer: from tumourigenesis to treatment

Objective

Age is cancer's primary risk factor and a significant determinant of how the resulting disease presents and progresses. Yet the specific contribution of ageing’s diverse hallmarks to this phenomenon is poorly defined. Circadian rhythms are a conserved adaptation that enables organisms to anticipate daily environmental cycles and thus mitigate their harmful effects on the body. However, in recent years, a decay of homeostatic cellular, tissue and systemic circadian rhythms has emerged as a hallmark of mammalian ageing. Concurrently, in the context of cancer, circadian inputs from the host are known to drive daily rhythms in tumour microenvironment composition, metastasis seeding and treatment response, whilst disruption of physiological circadian rhythms is itself an established tumour promoter. When considered together, this raises the intriguing possibility that ageing of the circadian system may reshape cancer circadian biology in a manner pertinent to its prevention or treatment. In particular, three key questions emerge: 1) Does ageing of the body and its circadian rhythm system change the tumourigenic potency of circadian rhythm disruption? 2) Are the circadian rhythms of an established tumour altered by ageing of the host and its circadian system? 3) If cancer circadian biology is rewired by ageing, can we identify where this change originates from? In CircTu-Age, we will combine cutting-edge models of ageing and cancer with targeted circadian rhythm disruption and circadian-omics to define how ageing impinges upon the circadian biology of cancer. This timely project will reveal the as-yet-uncharacterised interaction between an emerging hallmark of ageing, circadian rhythm decay, and the most common of age-related diseases, cancer. The knowledge generated by CircTu-Age will provide a roadmap for identifying interventions that diminish cancer risk later in life, and contribute to refining and expanding the burgeoning field of cancer chronotherapy.