Biological Electric Fields Guide Directional Migration and Promote Epithelial-Mesenchymal Transition in Lung Cancer

Background: Endogenous direct-current electric fields (dcEFs), as one of the essential biophysical signals that naturally occur in the tumor microenvironment, were previously demonstrated to suppress the cytotoxicity of the third-generation tyrosine kinase inhibitor osimertinib in epidermal growth factor receptor (EGFR)-mutant lung cancer.Materials and Methods: In the current study, we further investigated the electrotactic response of EGFR-mutant lung cancer with different osimertinib sensitivity, including osimertinib-sensitive PC-9GR cells and osimertinib-resistant PC-9GROR cells.Results: Firstly, in murine subcutaneous xenografts, robust endogenous electric currents were detected at the surface of tumors derived from osimertinib-resistant cells with a highly sensitive vibrating probe. Next, the electrotactic responses of two cell lines under EFs of different intensities were studied. Both PC-9GR and PC-9GROR cells exhibited directionally cathodal migration in a voltage-dependent manner, and osimertinib-resistant PC-9GROR cells displayed higher migration speeds. Epithelial-mesenchymal transition (EMT), which was previously reported to be closely related to tumor invasion and metastasis and could be suppressed by osimertinib, was enhanced under EF stimulation as reflected by increased vimentin and decreased E-cadherin in PC-9GR cells via western blotting and immunofluorescent staining regardless of osimertinib treatment. Additionally, pharmacological inhibition of phosphoinositide 3-kinase/protein kinase B (AKT) signals reduced electrotaxis and EMT.Conclusion: Taken together, these results suggested that activation of AKT pathway may play an important role in electrotaxis and EMT of EGFR-mutant lung cancer.