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 signalling pathway activity. Delineating the interface between morphology and signalling 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 employ a network-systems approach to integrate imaging data and RNA-seq expression data. Our workflow allows the discovery of unbiased and context-specific gene expression signatures and cell signalling sub-networks 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 signalling 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 signalling by numerous kinase and transcriptional regulators. Further analysis of our network implicates a gene expression module enriched in the RAP1 signalling 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.

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