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存活下来。然而，雌激素阳性（ER+）乳腺癌是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治疗失败导致的早期死亡，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，这些癌细胞处于休眠状态，传统的癌症治疗方法无法靶向它们。细胞可塑性是一种细胞现象，细胞在细胞状态之间表现出可逆的转变，这可能是细胞对当前治疗产生耐药性的问题的基础，也是细胞进入和退出休眠的原因。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力学中潜在的流动性引起的。这种流动性可以表现为振荡基因表达，是一些基于负反馈、生物延迟和分子组分不稳定性的基因表达网络的固有特性。在生物信息学筛选中使用这些标准，我们已经确定并验证了乳腺癌背景下的新型振荡基因。在这个项目中，我们的目标首先是了解我们已经确定的一个关键振荡基因，抑制因子1沉默转录因子（REST）的动态基因表达。REST已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创建。然后，我们的目标是利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休眠退出。直觉和生物学方法不足以理解复杂的动态行为，因此我们将使用尖端实验和数学理论的结合。

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.