Longitudinal Multi-Omic Data Integration for the Study of Evolutionary Dynamics and Awakening in Hormone Dependent Breast Cancer.

复发仍然是雌激素受体阳性(ER)乳腺癌的主要问题。在内分泌治疗停止后，复发的风险至少持续15年，并且复发率随时间保持稳定。这表明癌细胞亚群进入休眠，获得抗药性，然后随机苏醒，导致复发。大量的基因组、转录和表观遗传学图谱，以及单细胞表达和谱系追踪图谱，可以在室内从经历休眠觉醒动态的MCF7和T47D细胞株中获得，以响应内分泌治疗。之前对这些数据的分析已经强调了研究休眠细胞觉醒的重要性，纵向多组数据集成可能揭示推动这一过程的机制的新见解。我们的第一个目标将是应用已建立的统计机器学习方法并对其进行基准测试，包括降维、半监督数据集成和网络分析。为了我们的第二个目标，我们将在Evangelou小组的工作基础上开发新的数据整合统计方法。特别是，我们将考虑在数据集成方法中增加一个时间维度，这是目前未得到充分探索的多组数据集成领域。这种对时间数据的探索将让我们达到我们的第三个也是主要的目标，了解癌细胞从休眠到苏醒的潜在生物学和分子过程，并测试诸如表观遗传侵蚀等假说。

Relapse continues to be a major problem in oestrogen receptor positive (ER) breast cancer. Risk of relapse continues for at least 15 years after endocrine treatment discontinuation, and the recurrence rate remains stable across time. This points towards a subpopulation of cancer cells entering dormancy, acquiring resistance, and then stochastically awakening, leading to relapse. Genomic, transcriptomic and epigenetic profiles at bulk, along with single cell expression and lineage tracing profiles, are available in house from MCF7 and T47D cell lines undergoing dormancy-awakening dynamics in response to endocrine therapy. Previous analyses of this data have highlighted the importance of studying the awakening of dormant cells, and longitudinal multi-omic data integration could unveil new insights into the mechanisms driving this process. Our first aim will be to apply and benchmark established statistical machine learning approaches, including dimensionality reduction, semi-supervised data integration and network analysis. For our second aim, we will develop novel statistical methods for data integration building on the work of the Evangelou Group. In particular, we will consider the addition of a temporal dimension to data integration approaches, an area in multi omic data integration that is currently under-explored. This exploration of temporal data will let us address our third and main aim, understanding the biological and molecular processes underlying the evolution of cancer cells from dormancy to awakening and test hypotheses such as epigenetic erosion.