Abstract
Interactions between cells and their environment influence key physiologic processes such as their propensity to migrate. However, directed migration controlled by extrinsically applied electrical signals is poorly understood. Using a novel microfluidic platform, we found that metastatic breast cancer cells sense and respond to the net direction of weak (∼100 µV cm−1), asymmetric, non-contact induced Electric Fields (iEFs). iEFs inhibited EGFR (Epidermal Growth Factor Receptor) activation, prevented formation of actin-rich filopodia, and hindered the motility of EGF-treated breast cancer cells. The directional effects of iEFs were nullified by inhibition of Akt phosphorylation. Moreover, iEFs in combination with Akt inhibitor reduced EGF-promoted motility below the level of untreated controls. These results represent a step towards isolating the coupling mechanism between cell motility and iEFs, provide valuable insights into how iEFs target multiple diverging cancer cell signaling mechanisms, and demonstrate that electrical signals are a fundamental regulator of cancer cell migration.
Highlights
Interactions between cells and their environment influence key physiologic processes such as their propensity to migrate
We showed the selective action of induced Electric Fields (iEFs) in two triple-negative metastatic cell lines (MDA-MB-231, MCF10CA1a) and contrasted them with effects on nontransformed epithelial breast cells (MCF10A). iEFs provide access to the interior of cells[39], and our results show differences in electrical characteristics of the cytoplasm depending on cell type and lineage
We showed that parallel iEFs potently hinder epidermal growth factor (EGF)(+) motility of MDA-MB-231, while iEFs, regardless of direction, lower EGF(+) induced increases in MCF10CA1a migration speeds, which in both cases returned to the levels of untreated controls
Summary
Interactions between cells and their environment influence key physiologic processes such as their propensity to migrate. A common approach for applying EFs to cells in vitro is with the contact-based electrodes These direct current EFs (dcEFs), which result in current flow, have been shown to stimulate migration and provide directional guidance cues to both normal and tumor cells[8]. Strong dcEFs can steer or reorient migrating cells, to our knowledge they have not been demonstrated to hinder or slow down migration driven by extrinsic drivers of motility such as chemokine gradients Another approach for electrically treating cells is with alternating EFs, which are generated in accordance with Faraday’s Law of electromagnetic induction[11]. It is important to recognize that even though inductively generated
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