E-Cadherin Regulates Mitochondrial Membrane Potential in Cancer Cells.

Hydari Masuma Begum,Chelsea Mariano,Hao Zhou,Keyue Shen

doi:10.3390/cancers13205054

Abstract

Simple SummaryCancer cells have unusually high mitochondrial membrane potential (ΔΨm). However, the microenvironmental mechanisms that regulate cancer cell ΔΨm 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 ΔΨm.Epithelial cancer cells often have unusually higher mitochondrial membrane potential (ΔΨm) than their normal counterparts, which has been associated with increased invasiveness in vitro and higher metastatic potential in vivo. However, the mechanisms by which ΔΨm 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 ΔΨm. We found that micropatterning resulted in a spatial distribution of ΔΨm, which correlated with the level of E-cadherin mediated intercellular adhesion. There was a stark contrast in the spatial distribution of ΔΨm 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 ΔΨm 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 ΔΨm at the micropattern center. These results show that E-cadherin plays an important role in regulating the ΔΨm of cancer cells in the context of biophysical cues in TME.

Highlights

Epithelial cancer cells have higher mitochondrial membrane potential (∆Ψm ) than their normal counterpart cells [1], which has been associated with cancer stem cell features, increased secretion of angiogenic factor, and matrix metalloproteinase, as well as higher invasiveness in vitro [2,3,4,5]
We show that pathways related to E-cadherin-mediated adherens junctions (AJs) are differentially regulated at the edge vs. center of the tumor model, and that E-cadherin expression correlates with ∆Ψm spatial distribution
We have previously established a micropatterning platform, the micropatterned tumorstromal assay, to recapitulate tumor-stromal interactions [16], and demonstrated a spatial gradient of ∆Ψm in MCF-7 breast cancer cells within the tumor island surrounded by bone marrow stromal cells (BMSCs) [6]

Summary

Introduction

Epithelial cancer cells have higher mitochondrial membrane potential (∆Ψm ) than their normal counterpart cells [1], which has been associated with cancer stem cell features, increased secretion of angiogenic factor, and matrix metalloproteinase, as well as higher invasiveness in vitro [2,3,4,5]. We have previously reported in a xenograft metastatic breast cancer model in mice that cancer cells with higher ∆Ψm result in a greater lung metastatic burden than those with low ∆Ψm [6]. Together, these results highlight the biological significance of ∆Ψm in cancer cells. Recent studies show an emerging role of mechanical cues from the TME such as ECM stiffness in influencing cancer cell metabolism through mechanotransduction, adhesion receptor signaling, and cytoskeletal reorganization [15]. We showed that the physical confinement from TME downregulates ∆Ψm in cancer cells, while the

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