Abstract
The circadian clock regulates diverse physiological processes by maintaining a 24-h gene expression pattern. Genetic and environmental cues that disrupt normal clock rhythms can lead to cancer, yet the extent to which this effect is controlled by the cancer cells versus non-malignant cells in the tumor microenvironment (TME) is not clear. Here we set out to address this question, by selective manipulation of circadian clock genes in the TME. In two different mouse models of cancer we find that expression of the core clock gene Per2 in the TME is crucial for tumor initiation and metastatic colonization, whereas another core gene, Per1, is dispensable. We further show that loss of Per2 in the TME leads to significant transcriptional changes in response to cancer cell introduction. These changes may contribute to a tumor-suppressive microenvironment. Thus, our work unravels an unexpected protumorigenic role for the core clock gene Per2 in the TME, with potential implications for therapeutic dosing strategies and treatment regimens.
Highlights
The circadian clock is an endogenous, evolutionally conserved and ubiquitously expressed pacemaker, consisting of cell autonomous clocks and a central pacemaker located in the hypothalamus suprachiasmatic nucleus (SCN)
A disrupted circadian clock is associated with tumorigenesis, and cancer cells are thought to express a less robust clock compared to non-malignant cells (Welsh et al, 2004; Kiessling et al, 2017)
We found that deletion of Per1 and Per2 impairs cell rhythmicity (Figures 1E,F)
Summary
The circadian clock is an endogenous, evolutionally conserved and ubiquitously expressed pacemaker, consisting of cell autonomous clocks and a central pacemaker located in the hypothalamus suprachiasmatic nucleus (SCN). Together these clocks synchronize numerous biological processes between the organism and its environment. Amongst these processes are DNA damage repair, metabolism, and cell cycle (Blakeman et al, 2016). The circadian clocks act as oscillators to drive 24-h rhythms in gene expression and protein function, and these rhythms help the organism maintain a homeostatic relationship with the environment (Padmanabhan and Billaud, 2017). The toxicity and efficacy of various cancer therapies is dictated by time-of-day
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