A team of researchers from Berkeley University and Lawrence Berkeley National Laboratory has discovered that the EphA2/ephrin-A1 signaling complex, known as a participant in a number of human cancers, can be influenced through the careful application of physical force. This is quite phenomenal considering that until now only chemical reactions were known to influence signaling systems.
From a Berkeley Lab press release:
Observations have indicated that mammalian cells are sensitive to the physical aspects of their environment, such as the texture or geometry of the surrounding tissue. However, evidence that physical forces impact freely-moving signaling molecules (as opposed to focal adhesion molecules) in the membranes of cells has been lacking because the cell membrane is an environment that has always been difficult to characterize and manipulate. Groves and his research group have found a way to overcome this obstacle with the development of unique synthetic membranes constructed out of lipids and assembled onto a substrate of solid silica that enables them to directly control cellular signaling activities.
In this latest study, Groves and his colleagues worked with mammary epithelial cells from a library of 26 model human breast cancer cell lines that have been well-characterized by co-author Gray and his research groups at Berkeley Lab and UC San Francisco.
To test the sensitivity of the EphA2/ephrin-A1 signaling complex to mechanical forces, Groves and his group patterned their silica substrates with chromium metal lines that were 10 nanometers in height and 100 nanometers wide. These metal lines acted as diffusion barriers that impeded the lateral mobility of the EphA2/ephrin-A1 complexes in the synthetic membrane. The movement and spatial organization of the complexes were subsequently tracked through a combination of Total Internal Reflection Fluorescence (TIRF), reflection interference and epifluorescence imaging techniques.
“Without the barriers, the clusters of EphA2/ephrin-A1 signaling complexes were transported to the center of the cell–supported membrane junction, but with the barriers in place, there was an accumulation of clusters at the barrier boundaries,” Groves says. “This resulted in a spatial reorganization that altered the cell’s biochemical behavior.”
Quantitative analysis of these changes to the spatial organization of the EphA2/ephrin-A1 signaling complexes across the library of breast cancer cell lines revealed a strong correlation with the potential for metastasis. Since the patterned metal lines in the silica substrate are analogous to the stiffness, texture and other elastic and mechanical properties of tissue, as well as to internal structures within the cell membrane, the results of this study point to intriguing new possibilities for breast and other cancer therapies.
Image caption: Metal lines patterned into a silica membrane beneath a cell act as a diffusion barrier, impeding the mobility of EphA2/ephrin-A1 signaling complexes so they accumulate along the boundaries of the barrier. Without the barrier, the complexes are transported to a centralized location within the cell.
Press release: Berkeley Scientists Find New Way to Get Physical in the Fight Against Cancer …
Abstract in Science: Restriction of Receptor Movement Alters Cellular Response: Physical Force Sensing by EphA2
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