Circadian clockwork dysfunction in cancer: from molecular characterization to chronotherapeutic vulnerabilities

Circadian rhythms have emerged in recent years as key regulators of several cancer hallmarks, such as enhanced proliferation, metabolic rewiring and drug resistance. Circadian disruption is in fact closely linked to cancer initiation and progression, thus there is a growing interest in understanding how the molecular clock can influence oncogenesis. Cancer stem cells (CSCs) in particular display a peculiar circadian disruption, suggesting how the lack of clockwork functionality could be a key factor in conferring self-renewal, metastatic and drug resistance phenotypes. This study aimed to investigate how circadian rhythm alterations affect proliferation and metabolism, in the sake to unveil the contribution of the clock to CSCs survival and drug response, uncovering potential therapeutic vulnerabilities. The circadian phenotype of Differentiated and CSCs from bladder cancer, osteosarcoma and breast cancer was characterized using molecular biology and biochemical approaches, unveiling a profound alteration and downregulation of cell-autonomous circadian oscillations present in the differentiated counterparts. A robust proliferation rate circadian pattern emerged in differentiated cancer cells, that was in turn abrogated in CSCs; pharmacological modulation of core clock genes was able to induce a cytotoxic response in differentiated cancer cells, while the clock deregulation rendered CSCs refractory to clock-inducing drugs. The lack of clock control over metabolism was reflected by uncontrolled and aberrant swings in the glycolytic activity, resulting in a plastic bioenergetic phenotype displayed by CSCs. The present study confirmed the profound alterations of clockwork functionality in CSCs and how they impact cell proliferation and metabolic rewiring, as well as conferring resistance to possible chronotherapeutic interventions. More studies are needed to understand how to potentially combine chronotherapy and conventional chemotherapy in order to eradicate CSCs.