Begum Hydari Masuma, Mariano Chelsea, Zhou Hao, Shen Keyue
Department of Biomedical Engineering, Viterbi School of Engineering, University of Southern California, Los Angeles, CA 90089, USA.
USC Stem Cell, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
Cancers (Basel). 2021 Oct 9;13(20):5054. doi: 10.3390/cancers13205054.
Epithelial cancer cells often have unusually higher mitochondrial membrane potential (ΔΨ) 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 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. We found that micropatterning resulted in a spatial distribution of ΔΨ, which correlated with the level of E-cadherin mediated intercellular adhesion. There was a stark contrast in the spatial distribution of ΔΨ 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 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 at the micropattern center. These results show that E-cadherin plays an important role in regulating the ΔΨ of cancer cells in the context of biophysical cues in TME.
上皮癌细胞的线粒体膜电位（ΔΨ）通常比其正常对应细胞异常高，这与体外侵袭性增加和体内更高的转移潜能有关。然而，肿瘤微环境（TME）中癌细胞ΔΨ的调节机制仍不清楚。在本研究中，我们使用体外微图案化平台来重现TME中的生物物理限制线索，并研究这些线索调节癌细胞ΔΨ的机制。我们发现微图案化导致了ΔΨ的空间分布，这与E-钙黏蛋白介导的细胞间黏附水平相关。与高表达E-钙黏蛋白的（MCF-7）癌细胞相比，E-钙黏蛋白阴性的乳腺癌细胞（MDA-MB-231）微图案中ΔΨ的空间分布存在鲜明对比。E-钙黏蛋白黏附的破坏和敲除挽救了在高表达E-钙黏蛋白的MCF-7微图案中心发现的低ΔΨ，而在MDA-MB-231和MCF-7细胞中过表达E-钙黏蛋白则降低了它们在微图案中心的ΔΨ。这些结果表明，在TME的生物物理线索背景下，E-钙黏蛋白在调节癌细胞的ΔΨ中起重要作用。
