Bioinformatics approach to establish a new graph-based Wnt model for metastasis formation in breast cancer

Wnt信号通过β-连环蛋白依赖和独立的途径发生。WNT途径的基因在乳腺癌的所有分子亚型中都有过度表达，这些分子亚型后来转移到大脑。通过对乳腺癌脑转移的直接分析，我们已经表明β-连环蛋白非依赖性信号在这方面是重要的。然而，关键的WNT配体还不能确定，并且仍然缺乏调控这些事件的确切模型。因此，该项目的目的是建立WNT信号及其在乳腺癌中的不同亚通路的生物信息学模型。该模型将被描述为有向图。这张图将包含在β-连环蛋白依赖和独立的WNT信号中重要的分子及其作为节点(顶点)的调节靶标，以及作为边的不同类型的分子相互作用或调节机制。现有数据不支持系统生物学中经常使用的动态定量模型。因此，我们计划首先开发一个生物聚焦的WNT信号的定性模型。为此，将生成自己的生物数据。这些自身的数据以及外部乳腺癌数据集(来自GEO数据库的基因表达数据和蛋白质-蛋白质相互作用)将被整合到WNT模型中。由此产生的模型将考虑WNT信号的不同子路径以及相关性。这个基于图表的WNT模型的临床相关性将使用乳腺癌原发和转移的外部数据集进行评估。在与其他子项目(SP)的协作下，已建立的通路激活方法将应用于FOR942内的其他模型。

WNT signaling occurs via β-catenin dependent and independent pathways. Genes of the WNT pathway are overrepresented in all molecular subtypes of breast cancer primaries which later metastasize to the brain. Through the direct analysis of breast cancer brain metastases we have shown that β-catenin independent signaling is important in this context. However, the critical WNT ligand could not be identified and an exact model of the regulation of these events is still lacking. Thus, the aim of the project is to establish a bioinformatic model of WNT signaling and its different sub-pathways in breast cancer. The model will be described as a directed graph. This graph will contain the molecules important in β-catenin dependent and independent WNT signaling and its regulated targets as nodes (vertices) and the different types of molecular interactions or regulation mechanisms as edges. Available data do not allow a dynamic quantitative model, as frequently used in Systems Biology. We therefore plan to first develop a biologically focused qualitative model of WNT signaling. For this purpose, own biological data will be generated. These own data as well as external breast cancer datasets (gene-expression data from the GEO database and protein-protein interactions) will be integrated into the WNT model. The resulting model will consider the different sub-pathways of WNT signaling as well as dependencies. The clinical relevance of this graph-based WNT model will be evaluated using external data sets of breast cancer primaries and metastases. In collaboration with other subprojects (SPs) the established pathway activation approach will be applied to other models within the FOR 942.