E-Cadherin Regulates Mitochondrial Membrane Potential in Cancer Cells

SIMPLE SUMMARY: Cancer cells have unusually high mitochondrial membrane potential (ΔΨ(m)). However, the microenvironmental mechanisms that regulate cancer cell ΔΨ(m) remain unclear. In this study, we use in vitro micropatterned tumor models to mimic the confinement cues in tumor microenvironments and show that the E-cadherin mediated intercellular adhesion negatively regulates cancer cell ΔΨ(m). ABSTRACT: Epithelial cancer cells often have unusually higher mitochondrial membrane potential (ΔΨ(m)) than their normal counterparts, which has been associated with increased invasiveness in vitro and higher metastatic potential in vivo. However, the mechanisms by which ΔΨ(m) in cancer cells is regulated in tumor microenvironment (TME) remain unclear. In this study, we used an in vitro micropatterning platform to recapitulate biophysical confinement cues in the TME and investigated the mechanisms by which these regulate cancer cell ΔΨ(m). We found that micropatterning resulted in a spatial distribution of ΔΨ(m), which correlated with the level of E-cadherin mediated intercellular adhesion. There was a stark contrast in the spatial distribution of ΔΨ(m) in the micropattern of E-cadherin-negative breast cancer cells (MDA-MB-231) compared to that of the high E-cadherin expressing (MCF-7) cancer cells. Disruption and knockout of E-cadherin adhesions rescued the low ΔΨ(m) found at the center of MCF-7 micropatterns with high E-cadherin expression, while E-cadherin overexpression in MDA-MB-231 and MCF-7 cells lowered their ΔΨ(m) at the micropattern center. These results show that E-cadherin plays an important role in regulating the ΔΨ(m) of cancer cells in the context of biophysical cues in TME.