An unusual collaboration between cell and developmental biologists and physicists at UNC-Chapel Hill is providing insights into the relationship between the physical properties of cells and the signals that influence cell behavior.
In a paper published online May 15 in the journal Nature Cell Biology, a team led by Keith Burridge, PhD, Kenan distinguished professor of cell and developmental biology and a member of UNC Lineberger Comprehensive Cancer Center, and Richard Superfine, PhD, Taylor-Williams distinguished professor of physics and astronomy, demonstrates that exerting mechanical force on cells activates Rho GEF proteins through distinct signaling pathways. The Rho GEFs activate Rho proteins that are part of the RAS superfamily -- a class of proteins associated with cancer activity.
The cross-disciplinary team applied magnetic particles to cells and then used magnets to exert force on the cells -- creating extracellular tension.
"This experiment was only possible because we were able to bring together a team of physicists and cell biologists," said Burridge.
"It's very exciting because we have identified the entire pathway between the tension exerted on the cell to proteins that, in turn, activate other proteins that we know tend to be hyperactive in cancer," he added.
Scientists have long believed that the mechanical environment of cells affects their growth and properties. For example, solid tumor cells tend to have an altered stiffness. Other researchers have shown that the stiffer the cell matrix, the worse the prognosis. There is evidence that rigid tumors shed more cells, which escape the original tumor site and may lead to a greater chance of cancer spreading through metastasis.
"There has been a hypothesis that cell stiffness and tension create a vicious cycle leading to enhanced growth, more cell density, more tension, and larger tumors," said Burridge. "Innovation funding from the University Cancer Research Fund allowed us to identify the pathway and provided data that resulted in a grant renewal worth approximately $1.3 million over the next four years."
In addition to Burridge and Superfine, the research team included postdoctoral fellow Christophe Guilluy, PhD, and assistant professor Rafael Garcia-Mata, PhD, from the Department of Cell and Developmental Biology and graduate student Vinay Swaminathan, PhD, and assistant professor E. Timothy O'Brien, PhD, from the Department of Physics and Astronomy.
In addition to the UCRF innovation grant, this research was supported by the National Institutes of Health and a Marie Curie Outgoing International Fellowship from the European Union Seventh Framework Programme.
- Christophe Guilluy, Vinay Swaminathan, Rafael Garcia-Mata, E. Timothy O’Brien, Richard Superfine, Keith Burridge. The Rho GEFs LARG and GEF-H1 regulate the mechanical response to force on integrins. Nature Cell Biology, 2011; DOI: 10.1038/ncb2254
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