Molecular biosciences assistant professor Daniel Dickinson, who joined UT this fall, studies how disruptions in cell organization contribute to the spread of cancer throughout the body. In August, he received a $2 million grant from the Cancer Prevention and Research Institute of Texas, or CPRIT, for this work.
Dickinson’s research involves cell polarization, or the sequestering of cell contents and proteins to different sides of or locations within a cell. Nearly all cells are polarized, giving them properties such as inner and outer-facing ends or symmetry along an axis.
“When you have polarized cells, that means you have different things happening at different parts of the cell,” molecular biosciences professor David Stein said. “Many basic aspects of physiology … require cell polarity. If cells don’t have polarity, organs don’t function properly, embryos don’t develop properly and cells wouldn’t function properly.”
One good example of cell polarity is in epithelial cells, such as skin or intestinal cells, Stein said. For instance, the outside-facing half of intestinal cells are in charge of excreting digestive enzymes, whereas the inner half anchors the cell in place.
“If you think about a rectangle, there’s going to be two halves of that rectangle … one is the outside projecting into space, the other one is what’s stuck to all the other cells,” Stein said.
Cell polarity is established early in embryo development when different proteins migrate to different sides of a cell to establish polarity, Dickinson said. This segregational process allows cells to specialize and differentiate into the various cell types that we see in our bodies.
“There’s this whole complicated signal transduction network that helps cells interpret spatial information,” Dickinson said. “It helps them know which direction is which and organize their contents accordingly.”
These signal transduction pathways involve various proteins informing each other of where to go and what to do, Dickinson said. However, while it’s relatively easy to determine which proteins are involved in these pathways, scientists aren’t always able to tell how they’re involved or what role they play.
“We know a lot of genes (for these proteins) that, when you knock them out, will cause cells to have problems generating polarity,” Dickinson said. “But what we’re missing is a clear understanding of the physical interactions between all those signaling proteins. Who binds to who?”
The device that won Dickinson the CPRIT grant allows scientists who have identified proteins involved in these polarization pathways to also figure out which proteins interact with each other and when, Dickinson said.
“We can take a cell doing the behavior it normally does (and) break it open in a very small volume,” Dickinson said. “(Our device) has antibodies attached to the bottom, and these antibodies will selectively retrieve the proteins of interest from the solution.”
Each protein being studied is modified ahead of time to glow a certain color, Dickinson said. Under a powerful microscope, the sample is flashed with high-intensity lights, causing the proteins to appear as glowing specks. When these dots appear, different proteins can be distinguished from each other because they glow different colors.
“And then we just count,” Dickinson said. “So let’s say we’ve got 10,000 molecules of protein X in the sample, and 4,500 of them are (bound to) protein Y.”
Snapshots of the number and combinations of different proteins can then be taken at different stages in a cell’s development, giving researchers a sense of how and when proteins are interacting, Dickinson said.
“Knowing the parts that make something up is like knowing what the parts of an automobile are,” Stein said. “It tells you something, but in order to generate an automobile, you have to know how to put them together.”
Cell polarity allows cells to know where to go and which cells to attach to, Stein said. When signal transduction pathways in cancer cells are disrupted, the cells lose their sense of direction and can metastasize, or spread to other parts of the body.
“You need to have this adhesion,” Stein said. “When polarity breaks down, you lose some of these adhesive molecules, so now these cells don’t stick as well … that’s one of the things that allows them to free themselves and move around.”
In addition to continuing his research on cell polarity in healthy cells, Dickinson said he plans to use the grant money to expand his research into cancerous cells where that healthy polarity is disrupted.
“What’s really exciting about having the CPRIT grant is that we’ll be able to work on both of those questions in one lab,” Dickinson said.