Abstract
Breast cancer is one of the most prevalent types of cancers worldwide and yet, its pathophysiology is poorly understood. Single-cell electrophysiological studies have provided evidence that membrane depolarization is implicated in the proliferation and metastasis of breast cancer. However, metastatic breast cancer cells are highly dynamic microscopic systems with complexities beyond a single-cell level. There is an urgent need for electrophysiological studies and technologies capable of decoding the intercellular signaling pathways and networks that control proliferation and metastasis, particularly at a population level. Hence, we present for the first time non-invasive in vitro electrical recordings of strongly metastatic MDA-MB-231 and weakly/non-metastatic MCF-7 breast cancer cell lines. To accomplish this, we fabricated an ultra-low noise sensor that exploits large-area electrodes, of 2 mm2, which maximizes the double-layer capacitance and concomitant detection sensitivity. We show that the current recorded after adherence of the cells is dominated by the opening of voltage-gated sodium channels (VGSCs), confirmed by application of the highly specific inhibitor, tetrodotoxin (TTX). The electrical activity of MDA-MB-231 cells surpasses that of the MCF-7 cells, suggesting a link between the cells’ bioelectricity and invasiveness. We also recorded an activity pattern with characteristics similar to that of Random Telegraph Signal (RTS) noise. RTS patterns were less frequent than the asynchronous VGSC signals. The RTS noise power spectral density showed a Lorentzian shape, which revealed the presence of a low-frequency signal across MDA-MB-231 cell populations with propagation speeds of the same order as those reported for intercellular Ca2+ waves. Our recording platform paves the way for real-time investigations of the bioelectricity of cancer cells, their ionic/pharmacological properties and relationship to metastatic potential.
Highlights
Cancer is one of the major killers of humans with many problems remaining in its clinical management, from primary diagnosis to treatment of advanced disease
By using the pharmacological inhibitor TTX, we show that the asynchronous spikes are primarily caused by the opening and closing of the voltage-gated sodium channels (VGSCs), in direct agreement with VGSC expression occurring in Breast cancer (BCa) cells of strong metastatic potential (Fraser et al, 2005)
The sensor comprises two circular electrodes, with one of the electrodes acting as a measuring electrode and the other serving as a counter electrode
Summary
Cancer is one of the major killers of humans with many problems remaining in its clinical management, from primary diagnosis to treatment of advanced disease. A strongly metastatic and aggressive form of BCa is the triple-negative breast cancer (TNBC), where genes for the estrogen receptor (ER) and progesterone receptor (PR) are not expressed, and there is no amplification of the human epidermal growth factor receptor 2 (HER2) (Perou et al, 2000; Lee and Djamgoz, 2018). This renders TNBC difficult to treat as the commonly applied hormone therapies rely on targeting at least one of these three receptors (Al-Mahmood et al, 2018). These cells exhibit in vitro characteristics representative of cancer cell behavior in vivo (Sever and Brugge, 2015)
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