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With Halloween soon approaching, children and adults everywhere are preparing to disguise themselves in costumes to transform into someone or something else. Unlike the disguises we wear once a year, cells can make continuous strides to transform into malignant cells that metastasize to other areas of the body. Cancer cells that break away from a primary tumor and spread to secondary sites during metastasis have led to an estimated two-thirds of solid tumor-related deaths. Successfully stopping this spread requires a better understanding of how cells reach this deadly migratory state at both the cellular and molecular level.
During metastasis, cells typically use a process known as epithelial-to-mesenchymal transition (EMT) to switch from an epithelial or non-migratory state to a mesenchymal or motile state. In EMT, cell components such as the actin cytoskeleton, plasma membrane, and adhesion molecules work closely together to gain traction on cancer microenvironments or other cells. Proteins such as ezrin, radixin, and moesin (ERM) family proteins then help reversibly orchestrate the linkage between the plasma membrane and the actin cytoskeleton and allow the cell to move in a certain direction. Epithelial cells, therefore, use EMT to disguise themselves into a physical and molecular state that makes them more invasive and metastatic than they originally were before. Scary, isn’t it?
While there are typically clear molecular markers that signify that an epithelial cell has undergone EMT, physical parameters such as whether a cell appears more irregular in shape have been challenging to observe without using tools that allow researchers to quantify cells at the micro- and nanoscale. A recent study has used these tools to reveal a novel role of a physical parameter indicating whether an epithelial cell has migratory tendencies, termed membrane tension. Membrane tension contains the stretching and compressive forces applied at every point of the plasma membrane. Multiple cellular components work together to effectively increase the membrane tension, leading to cell stiffening, which prevents the high flexibility that a cell needs to migrate. The study, published in Nature Communications, showed that membrane tension acts as a mechanical switch to suppress or enhance cell migration, tumor invasion, and metastasis in a process spookily similar to EMT.
The authors first compared the tether force at the plasma membrane of various epithelial and mesenchymal cells using optical tweezers, which allows researchers to estimate membrane tension to a high degree of accuracy. They found that epithelial cells had higher membrane tension than their migratory counterparts due to a strengthened link between the actin cytoskeleton and ERM proteins. After removing these ERM proteins in epithelial cells, the authors found that cells lost their rounded shapes and transitioned to an elongated phenotype, exhibiting a marked increase in migratory potential, all while retaining epithelial-like molecular markers. Thus, by disrupting proteins involved in maintaining cell shape, non-migratory cells were disguised as motile ones.
To confirm that membrane tension is likely the cause of this EMT-like switch in epithelial cells, the authors either “dressed up” metastatic cells to appear as epithelial cells or did the reverse to stimulate EMT. Metastatic cells were first disguised to appear as epithelial cells by changing the naturally occurring function of an ERM protein. Although this ERM protein detaches from the plasma membrane in metastatic cancer cells, the authors created a molecular construct of the protein that indefinitely sticks to the plasma membrane of metastatic cells while remaining in an activated state to simulate epithelial-like cells. Compared to unaltered metastatic cells, these mutants lost their mesenchymal-like appearance and decreased in motility, while membrane tension significantly increased. After injecting these disguised cells into mouse models of human breast and lung tumors, the authors found that cells displayed a reduction in metastases and significantly smaller tumors were produced. Conversely, when the cellular switch from epithelial to mesenchymal was made, membrane tension, as well as the link between ERM proteins and actin decreased. Regardless of the environment in which these experiments were performed, high membrane tension was sufficient to suppress metastatic cell migration.
Since these experiments were performed with only a few different metastatic and non-metastatic cell types, the authors extended their studies to determine whether low membrane tension, influenced by the availability of ERM proteins, was a common trait across multiple cancers. For this, they evaluated the prevalence of ERM genes in datasets from The Cancer Genome Atlas and the Cancer Cell Line Encyclopedia, which included data from thousands of patients across 14 carcinomas. In addition, datasets containing ERM protein expression and patient survival of breast, lung, and gastric cancers were assessed. Surprisingly, the authors found a correlation between a high prevalence of ERM genes or proteins and malignant progression, which, from the results of this study, implies that high membrane tension may be an inherent physical feature of epithelial cells to prevent metastasis.
Beyond the well-established physical regulators of metastasis such as cell stiffness and shape, the authors reveal that membrane tension may also be a key player in hindering tumor formation and growth. This study opens multiple avenues for researchers to determine whether membrane tension could be a future target for cancer therapeutics.
Edited by Anthony Tao
Image created with Biorender.com
Primary work cited: Tsujita, K., Satow, R., Asada, S. et al. Homeostatic membrane tension constrains cancer cell dissemination by counteracting BAR protein assembly. Nat Commun. 12, 5930 (2021). https://doi.org/10.1038/s41467-021-26156-4