Circadian and cell cycle clock systems in cancer

生物钟和细胞周期是动态的生物事件。在过去的几十年里，随着数学模型的广泛发展和使用，我们对这些系统背后的分子机制的理解有了很大的提高。与之形成鲜明对比的是，对于这两个关键的振荡子如何相互作用，以及这些相互作用如何影响正常细胞或癌细胞的细胞增殖、DNA修复和凋亡，人们知之甚少。一方面，生物钟的紊乱会损害细胞生理和生活质量。另一方面，细胞周期的中断、DNA的修复或细胞凋亡会严重影响细胞和生物体的生存。实验和临床数据表明，昼夜节律紊乱会加速恶性肿瘤的增殖，而DNA损伤可以重置昼夜节律钟。因此，需要解决的一个核心问题是生物钟和细胞周期之间的相互作用如何影响正常细胞和癌细胞的细胞增殖和（基因）毒性敏感性，以及如何将这些知识转化为新的预防或治疗方法。C5Sys整合实验、数学和生物信息学方法，探索生物钟和细胞周期之间的动态联系，以及它们与正常和恶性细胞生理和增殖的相关性。C5Sys通过系统生物学（SB）方法绘制了这些相互作用和两个振荡系统之间的耦合。C5Sys研究了生物钟如何在正常细胞和癌细胞中充当细胞周期进程的看门人。这将导致确定这些时钟-细胞周期相互作用的新靶点，其内部或外部扰动可能影响癌症进展和/或可能影响癌症治疗。C5Sys汇集了7个欧洲团队，他们在生物钟、癌症动力学、DNA修复和细胞凋亡、生物信息学、数学模型、时间序列分析和成像等领域具有广泛的互补背景和广泛的国际科学认可。C5Sys被组织成5个工作包（WP），在WP内部和WP之间的实验、数学和统计团队之间有紧密的相互作用。C5Sys将：1)绘制昼夜节律和细胞周期时钟之间的关键相互作用节点，其破坏与改变或恶性增殖有关；2)表征信号通路的时间尺度，这对两种生物钟的耦合至关重要，包括那些在更高频率下工作的；3)确定其中断参与恶性生长的节律信号；4)提供一个集成的“增殖”细胞模型，包括昼夜节律和细胞周期时钟以及潜在的节律信号通路；5)确定癌细胞的模型特性；6)探索定向干预在破坏或加强生物钟和细胞周期耦合方面的相关性；7)尝试提供基于模型的时间治疗干预相关原理的体外和体内证明。新的细胞系、生物标志物监测方法和数学工具，将作为这一提议的结果而开发，将绕过目前在探索功能基因组学的时间变化及其对癌症的潜在治疗相关性方面的瓶颈。C5sys的结果将引发1)针对涉及昼夜节律和细胞周期系统的几种人类疾病的创新时间治疗研究；2)科学和生物医学应用的专用技术开发。

The circadian clock and the cell cycle are dynamic biological events. Over the last decades, our understanding of the molecular mechanisms underlying these systems has greatly improved, with extensive development and use of mathematical models. In sharp contrast, little is known about how these two crucial oscillators interact, and how these interactions affect cellular proliferation, DNA repair and apoptosis, 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 can profoundly impact 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. Therefore, a central question to be addressed is how interactions between the circadian clock and the cell cycle affect cellular proliferation and (geno)toxic sensitivity in normal and cancer cells, and how this knowledge translates into new prevention or treatments. C5Sys integrates experimental, mathematical and bioinformatic approaches to explore the dynamic links between circadian clock and cell cycle, and their relevance for normal and malignant cell physiology and proliferation. C5Sys maps these interactions and the coupling between both oscillatory systems through a systems biology (SB) approach. C5Sys investigates how the circadian clock can act as a gatekeeper of cell cycle progression in normal and cancer cells. This will result in the identification of novel targets for these clock-cell cycle interactions, whose internal or external perturbations could affect cancer progression and/or could impact on cancer treatments. C5Sys assembles 7 European teams with extensive complementary background and wide international scientific recognition in the fields of circadian clocks, cancer dynamics, DNA repair and apoptosis, as well as bioinformatics, mathematical models and time series analysis and imaging. C5Sys is organised in 5 workpackages (WP), with tight mutual interactions between experimental, mathematical and statistical teams within and between WPs. C5Sys will: 1) map critical interaction nodes between circadian and cell cycle clocks, whose disruption is relevant for altered or malignant proliferation; 2) characterize the time scales in the signalling pathways, which are critical for the coupling of both biological clocks, including those operating at higher frequency; 3) determine the rhythmic signals whose disruption participates in malignant growth; 4) provide an integrated 'proliferative' cellular model incorporating circadian and cell cycle clocks and underlying rhythmic signalling pathways; 5) determine model properties in cancer cells; 6) probe the relevance of targeted interventions for disrupting or reinforcing the coupling of circadian clock and cell cycle in silico; and 7) attempt to provide in vitro and in vivo proof of principles of the relevance of model-based chronotherapeutic interventions. The novel cell lines, biomarker monitoring methods and mathematical tools, which will be developed as a result of this proposal, will circumvent current bottlenecks in the exploration of temporal changes in functional genomics and their potential therapeutic relevance for cancer. C5sys results will trigger 1) innovative chronotherapeutic research for several human diseases involving circadian and cell cycle systems and 2) dedicated technology development for scientific and biomedical applications.