Cancer breakthrough uses CRISPR to target extra chromosomes
Yale scientists have discovered a new potential treatment avenue to fight cancer. Using CRISPR gene-editing, the team eliminated extra chromosomes from cancer cells and found that they could no longer grow out of control.
Healthy human cells have 23 pairs of chromosomes, but it’s been observed for over a century that the majority of cancer cells have extras. This condition is known as aneuploidy, but its exact role in cancer remained a mystery – was it a root cause of cancer or just a symptom of it? In a new study, scientists at Yale investigated that role.
“For a long time, we could observe aneuploidy but not manipulate it,” said Jason Sheltzer, senior author of the study. “We just didn’t have the right tools. But in this study, we used the gene-engineering technique CRISPR to develop a new approach to eliminate entire chromosomes from cancer cells, which is an important technical advance. Being able to manipulate aneuploid chromosomes in this way will lead to a greater understanding of how they function.”
To start with, the team focused on a type of aneuploidy where a cell gains a third copy of a structure called the “q arm” on chromosome 1. This mistake is found in multiple cancer types from an early stage and is linked to disease progression.
The researchers developed a tool they call Restoring Disomy in Aneuploid cells using CRISPR Targeting (ReDACT) and when they used it to eliminate these extra chromosomes, they found that the cells lost the ability to form malignant tumors. On closer inspection, they found a mechanism for why aneuploidy might boost cancer progression – specific genes that stimulate cancer growth were encoded on three chromosomes instead of the usual two.
Next, the team tested whether this mechanism could be exploited as a therapeutical target for cancer. A gene known as UCK2 has previously been found to be sensitive to certain drugs, and the researchers here found that this made cells with an extra copy of chromosome 1 (and therefore a third copy of UCK2) more sensitive to these drugs.
The team mixed normal and aneuploid cells into batches, with the latter making up 20% of the cells. They found that without intervention, the aneuploid cells would grow to comprise 75% of the batch after nine days. But when treated with drugs that target UCK2, aneuploid cells dropped to just 4% of the batch after nine days.
“This told us that aneuploidy can potentially function as a therapeutic target for cancer,” said Sheltzer. “Almost all cancers are aneuploid, so if you have some way of selectively targeting those aneuploid cells, that could, theoretically, be a good way to target cancer while having minimal effect on normal, non-cancerous tissue.”
Of course, this research is still in its very early days, having only been tested in cultured cells so far. But it’s an intriguing idea that could eventually unlock new cancer treatments, and the team is now working to move to animal tests.
The research was published in the journal Science.
Source: Yale University