The morphology of breast cancer cells is often used as an indicator of tumor severity and prognosis. Additionally, morphology can be used to identify more fine-grained, molecular developments within a cancer cell, such as transcriptomic changes and signaling pathway activity. Delineating the interface between morphology and signaling is important to understand the mechanical cues that a cell processes in order to undergo epithelial-to-mesenchymal transition and consequently metastasize. However, the exact regulatory systems that define these changes remain poorly characterized. In this study, we used a network-systems approach to integrate imaging data and RNA-seq expression data. Our workflow allowed the discovery of unbiased and context-specific gene expression signatures and cell signaling subnetworks relevant to the regulation of cell shape, rather than focusing on the identification of previously known, but not always representative, pathways. By constructing a cell-shape signaling network from shape-correlated gene expression modules and their upstream regulators, we found central roles for developmental pathways such as WNT and Notch, as well as evidence for the fine control of NF-kB signaling by numerous kinase and transcriptional regulators. Further analysis of our network implicates a gene expression module enriched in the RAP1 signaling pathway as a mediator between the sensing of mechanical stimuli and regulation of NF-kB activity, with specific relevance to cell shape in breast cancer.

中文翻译：

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从配对基因表达-细胞形状成像数据中识别表型特异性网络


乳腺癌细胞的形态通常被用作肿瘤严重程度和预后的指标。此外，形态学可用于识别癌细胞内更细粒度的分子发育，例如转录组变化和信号通路活性。描绘形态学和信号传导之间的界面对于理解细胞为了经历上皮-间质转变并最终转移而处理的机械线索非常重要。然而，定义这些变化的确切监管体系仍不清楚。在这项研究中，我们使用网络系统方法来整合成像数据和 RNA-seq 表达数据。我们的工作流程允许发现与细胞形状调节相关的公正且特定于背景的基因表达特征和细胞信号传导子网络，而不是专注于识别先前已知但并不总是具有代表性的途径。通过从形状相关的基因表达模块及其上游调节子构建细胞形状信号网络，我们发现了 WNT 和 Notch 等发育途径的核心作用，以及许多激酶和 Notch 精细控制 NF-kB 信号传导的证据。转录调节因子。对我们网络的进一步分析表明，RAP1 信号通路中富含的基因表达模块是机械刺激感知和 NF-kB 活性调节之间的中介，与乳腺癌细胞形状具有特定相关性。