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Researchers develop new method for tracking cell interactions

A group of Stanford researchers have developed a new technique for tracking cell interactions in living bodies, an advance that has significant implications for revealing information about the migration of metastatic cancer cells.

The researchers’ technique involves genetically altering cancer cells, which are also called reporter cells, and immune cells, dubbed activator cells. The activator cells were engineered to produce an enzyme that would convert caged luciferin into luciferin, a biological compound found in fireflies.

The reporter cells were altered to produce luciferase, an enzyme that would catalyze the luciferin produced by the activator cells and ultimately emit light. Ten mice were injected with the genetically altered reporter and activator cells as well as caged luciferin.

The research team was able to detect when and where the immune cells interacted with the metastatic cancer cells, as the specific areas in the mouse’s body would light up in indicating interaction between the activator and reporter cells.

The team’s results were published in a study co-authored by Mark Sellmyer Ph.D. ’10 M.D. ’12, Laura Bronsart P.D. ’08 ’12 Ph.D. ’14, former postdoctoral scholar Jennifer Prescher, visiting scholar Hiroshi Imoto, Professor of Pediatrics and of Microbiology and Immunology Christopher Contag and Associate Professor of Chemical and Systems Biology Thomas Wandless.

According to Prescher, the technique’s creation was motivated by the researchers’ struggles with tracking specific cell interactions in metastatic and infectious models because of the large number of interactions between cell populations in living bodies.

“We thought it would make our lives easier to only illuminate the interactions that we were most concerned about,” Prescher said. “There were no good ways to do that, so we had to repurpose existing technologies to skew the optical signals.”

Contag said that he, Sellmyer, Prescher and Wandless worked on developing the new technique between 2009 and 2011, spending a significant amount of time brainstorming ideas for creating the most efficient and widely-applicable method for tracking cell interactions.

“We tried a lot of different systems, but this ended up being the one that was the easiest and will be [the] one that hopefully other people can use in their labs, [and it is also] the fastest,” Sellmyer said, noting that many existing methods of tracking interactions between cells, such as implanting a microscope into a living body, are not very effective.

While the researchers’ new technique works well for tracking cell interactions in mice, Sellmyer said that it cannot yet be applied to humans, and instead functions primarily as a research tool for immunologists, cancer biologists and microbiologists.

“It’s limited by the penetration of light using the firefly protein. Mice are very small animals, so we can see the cells almost anywhere in the animal,” Sellmyer said. “Humans have much larger tissue depth that don’t allow the light to penetrate all the way through.”

According to Prescher, the barriers preventing this technology from being implemented in humans are quite significant.

“You would have to remove the skin and fat to have a chance to see the signal, and it also requires a genetically encoded protein from a firefly,” Prescher said. “We’re not at the point yet to be able to introduce a lot of transgenes into humans.”

However, she expressed confidence the technique could still be helpful in current cancer studies, especially as researchers delve further into the issue of why cancer reappears and metastasizes.

“I don’t think the cancer biology community has a good handle on why that is, where do the metastatic cells show up, why they show up and why can’t we predict that or treat that aspect of it,” Prescher said. “Imagine if we had ways to visualize that process, the most deadly aspect of cancer progression, and these types of tools that we’re developing give us a way to begin to see that better.”

Prescher said she will continue to work on gaining insight into the early steps of metastatic disease, noting that being able to collect more data on the movements of metastatic cells would be a “huge boon” for cancer research.

“You can test all sorts of therapeutics on metastatic disease or learn more about the cells that migrate around,” Prescher said. “Our tools can now start to give us a better vantage point of knowing when and where that occurs.”

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