Cancer cells re-engineered with CRISPR to destroy other tumour cells

CRISPR helped make the re-engineering cancer cells resistant & sensitive in different contexts.

In a striking new development, scientists at the Harvard Medical School have used the gene-editing tool CRISPR, to trick tumour cells into fighting their own kind.

Cancers cells from malignant tumours spread from the tumour site to other regions in the body by being picked up and circulated in the blood stream. It is now understood among researchers that these mobile tumour cells also have a 'tumour-homing' instinct — an ability to find their way and return to the tumour site of origin.

Researchers at Harvard have capitalised on this ability, and re-engineered cancer cells to secrete a protein that can trigger self-destruction in the tumour-resident cancer cells it encounters. The re-engineered cells, too, have a molecular suicide-switch that keeps them from growing into new tumours elsewhere. The re-engineering was done using CRISPR, the revolutionary gene-editing tool that enabled more than one breakthrough in biological research since it was developed for commercial use in 2012.

The new study, published in Science Translational Medicine on July 11 isn't the first attempt to get cancer cells to fight and kill their own kind. Many such studies in cancer research have also used tumour cells to deliver lethal viruses to non-circulating tumour cells, among others that went the way of charging up immune cells to target and fight tumours.

“The new twist here is the use of CRISPR-based technology to add resistance or sensitivity features to the parental cells,” says Renata Pasqualini, cancer biologist at Rutgers Cancer Institute in New Jersey. The novelty provided by use of CRISPR/Cas9 allows these cells to display artificial and sophisticated properties like the ability to trigger it's self-destruction pathway after having performed a certain task.

With this objective, researchers scanned for proteins that could trigger cell-death across cancer cell types. They found a suitable candidate in S-TRAIL, a protein which upon re-engineering cancer cells to overproduce, managed to kill off a range of cancer cell types while leaving healthy cells in the vicinity unharmed.

Representational image. Reuters

There team used a combination of two different approaches to test their theory.

One used tissue from an aggressive brain cancer, called glioblastoma, which was inherently resistant to S-TRAIL's toxic effects. Scientists re-engineering a sub-population of these glioblastoma cells using CRISPR to increase the number of S-TRAIL genes each of them has, thereby increasing the amount of S-TRAIL's protein made by the cell and its corresponding activity. This sub-population was then set loose on cancer cells that were sensitive to the S-TRAIL protein. While the re-engineered cells might trigger their suicide pathways sooner, the idea here is that the cells would take down as many cancer cells as it can before it dies.

The second approach also involved glioblastoma cells, to create an army of these cells that were sensitive to S-TRAIL’s effects. They removed the genes that imparted sensitivity to S-TRAIL in the army of cancer-fighting cells before adding in copies of the S-TRAIL gene so they overproduce the cancer cell-toxic protein just like in the first approach. This would give the cancer-fighting cells more resistance and durability than in the first approach.

The researchers found that both these approached to re-engineered cells did exactly what they intended for them to — reduce tumour sizes in a mouse model for cancer to a significantly higher degree compared to mice that didn't receive the treatment. The mice treated with the re-engineered cells did more than that — they also lived longer.

"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',” says study coauthor and stem cell researcher Khalid Shah. If and when made available, a therapy from the first approach used the study could enable doctors to collect patients’ cancer cells themselves, and personalise a patient's treatment by weaponizing his/her specific cancer to target itself. The second could be equally revolutionary, and will likely succeed even if not taken from the same tumour population, according to the researchers.

The technique could offer faster, cheaper and precise methods of cell therapies in cancer treatment.




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