Using gene editing, scientists have hoodwinked tumor cells into turning against their own kind.
Cancer cells circulating in the bloodstream have something of a homing instinct, able to find and return to the tumor where they originated. To capitalize on that ability, researchers engineered these roving tumor cells to secrete a protein that triggers a death switch in resident tumor cells they encounter. The cancer-fighting cancer cells also have a built-in suicide switch — so the weaponized cells self-destruct before they can start tumors of their own, the team reports in the July 11 Science Translational Medicine.
The new study isn’t the first attempt to fight cancer with cancer. Previous research has used circulating tumor cells to deliver cancer-killing viruses to noncirculating tumor cells, for example. But the new approach uses a gene-editing technology called CRISPR/Cas9 to manipulate the offensive-line cancer cells and give them more sophisticated properties, such as the ability to self-destruct once no longer needed.
Cells on the move
When circulating tumor cells (green) that are engineered with CRISPR to kill other tumor cells are injected into a mouse, they migrate over time to established tumor cells (red), as seen in these fluorescence photomicrographs.
“The new twist here is the use of CRISPR-based technology to add resistance or sensitivity features to the parental cells,” says Renata Pasqualini, a cancer biologist at Rutgers Cancer Institute of New Jersey in Newark.
Getting the technique to work took several steps. First, researchers hunted for a protein that could trigger cell death in many types of cancer cells. The winning candidate, a protein called S-TRAIL, killed off a variety of cancer cells and wasn’t particularly toxic to healthy cells.
Then, the team tested two different approaches. The first used glioblastoma (a kind of aggressive brain cancer) cells that were resistant to the effects of S-TRAIL. Researchers used CRISPR to edit genes in these tumor cells to make them produce lots of S-TRAIL, and then set the cells loose on cancer cells that were sensitive to the deadly protein.
In another approach, scientists took glioblastoma cells that were sensitive to S-TRAIL’s effects, and cut out the genes that impart that sensitivity before giving the cells the genes to produce the protein.
Both kinds of engineered cells reduced the size of tumors in mice compared with mice who didn’t get the treatment, the researchers found. Mice given the treatment lived longer, too.
Each approach has pros and cons, says study coauthor Khalid Shah, a stem cell researcher at Brigham and Women’s Hospital in Boston.
In a clinical setting — still a long way off for this research — using cells that aren’t yet resistant to S-TRAIL could be “a little bit cumbersome,” Shah says. It would enable doctors to collect patients’ own cancer cells, and then turn them into a weapon targeted against people’s specific cancer. But the wait time for that special cellular engineering might make the option a no-go for very sick patients.
The other approach, built with standard cells that are already resistant to S-TRAIL, could be stockpiled in hospitals for quick and easy access. But because those cells would be foreign to a patient, there would be a greater risk that the body would reject them.