Project: Circadian and cell cycle clock systems in cancer

Mammalian cells are endowed with biological oscillators which time their activities. The circadian clock (circa, about; dies, day) generates a 24-hour rhythm which controls both cellular metabolism and cell division. The cell division cycle is an oscillator which times DNA synthesis, mitosis, and related apoptosis and DNA repair. Our understanding of the molecular mechanisms at work in both oscillators has greatly improved. In sharp contrast, little is known about how these two crucial oscillators interact, and how these interactions affect cellular proliferation in normal or cancer cells. On the one hand, the disruption of circadian clocks impairs cell physiology and quality of life. On the other hand, disruption of cell cycle, DNA repair or apoptosis impacts on cell and organism survival. Experimental and clinical data show that circadian disruption accelerates malignant proliferation, and that DNA damage can reset the circadian clock. The central question addressed is how interactions between the circadian clock and cell cycle affect cellular proliferation and genotoxic sensitivity in normal and cancer cells, and how this knowledge translates into new prevention or therapeutic applications. Seven teams in France, Netherlands and United Kingdom integrate experimental, mathematical and bioinformatic approaches, so as to develop novel cell lines, biomarker monitoring methods and mathematical tools. C5Sys triggers innovative chronotherapeutic research for human cancers and advances systems medicine for improving patient care.

Acronym C5Sys
Project Results
(after finalisation)
In tissues such as bone marrow, intestinal mucosa or regenerating liver, the daily rhythm of cell division is controlled by the cell’s circadian clock. Determining how this clock organises important processes such as cell division, apoptosis and DNA damage repair is key to understand the links between circadian dysfunction and malignant cell proliferation. Moreover since traditional chemotherapeutic agents act by killing cells that are dividing and also harms healthy cells as a side effect, timing chemotherapy by the circadian clock offers the possibility of decreasing toxicity and increasing effectiveness in the treatment of cancer. In this project we investigated a range of issues across the spectrum from basic science to clinical practise. For example, at the clinical end we have shown for the first time that the circadian clock is a critical determinant for achieving several-fold improvements in chemotherapy tolerability through its delivery at an optimal circadian time. Although, the optimal drug timing has strong dependence upon sex and genetic background, mathematical modeling using circadian expression of clock genes Rev-erbα and Bmal1 as input data enables accurate prediction of optimal timing for the drug considered. On the basic science end, we showed that in proliferating mouse fibroblasts there is more than one way in which the clock and cell cycle synchronise their oscillations and that one of them is the biological equivalent of the phase-locking first discovered by Huygens in the 17th century when he coupled two clocks together. When phase-locked two coupled oscillators have a fixed relative phase and oscillate with a common frequency.
Network ERASysBio+
Call ERASysBio+-2008-01

Project partner

Number Name Role Country
1 Hospital Paul Brousse Coordinator France
2 Erasmus University Medical Center (ERM) Partner Netherlands
3 University College London (UCL) Partner United Kingdom
4 University of Nice Partner France
5 University Paris Sud 11 Partner France
6 Institut National de la Recherche en Informatique et Automatique Paris-Rocquencourt (INRIA) Partner France
7 University of Warwick Partner United Kingdom