Cell shape and the microenvironment regulate nuclear translocation of NF-κB in breast epithelial and tumor cells

Although a great deal is known about the signaling events that promote nuclear translocation of NF-kappa B, how cellular biophysics and the microenvironment might regulate the dynamics of this pathway is poorly understood. In this study, we used high-content image analysis and Bayesian network modeling to ask whether cell shape and context features influence NF-kappa B activation using the inherent variability present in unperturbed populations of breast tumor and non-tumor cell lines. Cell-cell contact, cell and nuclear area, and protrusiveness all contributed to variability in NF-kappa B localization in the absence and presence of TNF alpha. Higher levels of nuclear NF-kappa B were associated with mesenchymal-like versus epithelial-like morphologies, and RhoA-ROCK-myosin II signaling was critical for mediating shape-based differences in NF-kappa B localization and oscillations. Thus, mechanical factors such as cell shape and the microenvironment can influence NF-kappa B signaling and may in part explain how different phenotypic outcomes can arise from the same chemical cues.