Understanding the role and regulation of a tumour suppressor's oscillatory gene expression in cancer cell plasticity

乳腺癌治疗的进步意味着比以往任何时候都有更多的患者从癌症中幸存下来。然而，在雌激素阳性（ER+）乳腺癌中，最常见的乳腺癌类型，一些患者要么在治疗过程中对抗雌激素治疗产生耐药性，要么在治疗结束后复发。对治疗产生耐药性意味着由于治疗失败而导致的早期死亡，而复发意味着治疗方案结束后几年与癌症相关的生命损失。复发是由于一些癌细胞的重新觉醒而发生的，这些癌细胞变得休眠并且不被常规癌症治疗靶向。细胞可塑性是细胞现象，细胞显示出细胞状态之间的可逆转变，这可能是细胞对当前疗法产生抗性以及它们进入和退出休眠的问题的基础。但是细胞是如何获得这种可塑性的呢？基于我们对神经干细胞的研究，我们的假设是癌细胞的可塑性是由基因表达动态中的潜在流动性引起的。这种流动性，可以表现为振荡基因表达，是一些基因表达网络的固有属性，这些网络基于负反馈，生物延迟和分子成分的不稳定性。使用这些标准在生物信息学筛选，我们已经确定并验证了新的振荡基因在乳腺癌context.In这个项目中，我们的目标首先，了解如何动态基因表达的一个关键的振荡基因，我们已经确定，阻遏元件1沉默转录因子（REST）。REST已经被认为是一种肿瘤抑制因子，但其表达的动态特性尚未被研究过。我们将研究动态REST表达是否以及如何导致肿瘤内不同细胞状态的产生。然后，我们的目标是用新技术操纵该基因的表达动态，以便将细胞锁定在所需的状态，例如防止休眠或防止退出休眠。直觉和生物学方法不足以理解复杂的动力学行为，因此我们将使用尖端实验和数学理论相结合的方法。

Advances in breast cancer treatment mean that more patients survive cancer than ever before. However, in estrogen positive (ER+) breast cancer, the most common type of breast cancer, some patients either develop resistance to anti-estrogen therapies during the treatment itself or relapse after the end of treatment. Developing resistance to therapies means earlier mortality due to treatment failure while relapse means cancer-related loss of life a few years after the treatment regime is over. Relapse occurs due to the re-awakening of some cancer cells, which become dormant and are not targeted by conventional cancer therapy. Cell plasticity is cellular phenomenon whereby cells show reversible transitions between cell states may underlie the problems of cells becoming resistant to the current therapies, and also their entry into and the exit from dormancy. But how do cells acquire such plasticity? Our hypothesis, based on our work on neural stem cells, is that cancer cell plasticity is caused by an underlying fluidity in the dynamics of gene expression. This fluidity, which can manifest itself as oscillatory gene expression, is an inherent property of some gene expression networks that are based on negative feedback, biological delays and instability of molecular components. Using these criteria in a bioinformatic screen, we have identified and validated novel oscillatory genes in a breast cancer context.In this project, we aim first, to understand how dynamic gene expression of a key oscillatory gene that we have identified, the repressor element 1 silencing transcription factor (REST). REST is already known as a tumour suppressor but the dynamic propertied of its expression have not been studied before. We will examine whether and how dynamic REST expression leads to the creation of different cellular states within a tumour. Then, we aim to manipulate the dynamics of expression of that gene with new technologies in order to lock cells in a desired state, for example preventing dormancy or preventing exit from dormancy. Intuition and biological methods are not enough to understand complex dynamic behavior therefore we will use a combination of cutting-edge experiments and mathematical theory.