Remove just one gene in a cell and it can cause rapid, uncontrollable cell division — cancer. Animal immune systems have developed their own kind of police force to keep tumors in check. But what if a single gene, when deleted, could have the ability to stop even the most competent of immune systems from killing cancerous cells?
According to a recent study by researchers at the Yale Systems Biology Institute, the gene exists, and it has a name: Prkar1a.
Located on the bottom half of chromosome 11 in mice, Prkar1a codes for a protein that aids in the cell signal pathway. But when the team injected cells without the gene under the skin of mice, those cells rapidly grew into tumors that were able to evade normal immune responses. A gene like this is not new in itself — plenty of other genes are linked to cancer, such as Csnk1a1, Nf2 and Zbtb40 — but there’s more than meets the microscope with Prkar1a.
Not only is it relatively unknown compared to well-researched cancer-cell superstars, but cells without it also grew tumors more aggressive than every other cell line the researchers tested. By identifying the offending gene, cancer biologists have now come one step closer to understanding how cancer works. The study was published in the journal Cell Systems on Feb. 20.
For first author and member of the Sidi Chen Lab Adan Codina GRD ‘21, his team’s method of finding Prkar1a was more thorough than other genetic survey techniques.
“We are a lab in the Systems Biology Institute and so we take a systems biology approach to genetic testing,” he said. “This means investigating questions on a broader scale than the average lab.”
Prkar1a was one of over 80,000 different genes that the researchers tested in the study. For each experiment, Codina’s team used the genome editing tool, CRISPR Cas9, to delete a unique section of mice cell DNA and placed the affected cells into an incubator to divide. Then, researchers injected a group of around 20 million mutant cells under the skin of mice with varying levels of immune system competency. Of the cell lines they tested, 11 genes were found to have contributed to tumor growth in a statistically significant manner.
Out of that group, Codina said his team chose to focus on Prkar1a because the tumors its absence formed were particularly impressive.
“The cells could grow really aggressive tumors in the immune-competent mice that had functional T-cells, and none of the other genes that we looked at could do that,” he said. “This was a really big indicator that this was the gene that was worth following up on, because if performance is aggressive cancer, it was outperforming well-known genes that had lots of literature behind them.”
Indeed, Prkar1a is truly an underdog in the cancer research world. Compared to mouse gene Pten, which in the past five years has appeared in almost 500 different studies, just under 40 articles have been published about Prkar1a’s function in nonhumans in an identical period of time.
Because of its relative obscurity, according to Codina, the gene’s connection to cancer needs to be tested in more clinically relevant ways before scientists can map the findings to humans. For example, since tumors usually grow from within the mouse and not from foreign cells injected under the skin, researchers at the Systems Biology Institute plan on removing Prkar1a from liver cells to better understand how the gene’s absence can lead to cancer.
However, according to co-author and fellow member of the Sidi Chen Lab Paul Renauer GRD ’22, there is enough of a genetic similarity between mice and humans that basic assumptions of Prkar1a’s behavior in humans are not irrational.
“Our research results align with the previous knowledge of Prkar1a-loss, which has been derived from both human and [mouse] studies,” he said. “Additional work will be required to confirm our specific findings in human disease, yet this is the case with all disease model-based research.”
According to the National Center for Biotechnology Information, the DNA sequence for Prkar1a is over 20,000 base pairs long.
Matt Kristoffersen | email@example.com