The team replicates the CRISPR system in mice to eliminate tumor cells without affecting healthy cells

Representative images of an untreated tumor (left) compared to another tumor (right) treated with the CRISPR gene editing system for elimination of fusion genes. Cells are stained with a cell proliferation marker (Ki67). Brown staining indicates a high rate of cell proliferation in untreated tumors, whereas the absence of staining (cells in blue) indicates that CRISPR-treated tumors inhibited its growth. Sincerely: CNIO

The CRISPR / Cas9 gene-editing tool is the most promising approach to the treatment of genetic diseases – including cancer – an area of ​​research where progress is making progress. Now, the Molecular Cytogenetics Unit under the leadership of Sandra Rodríguez-Pereles at the Spanish National Cancer Research Center (CNIO) has taken a step forward by effectively applying this technology to eliminate the so-called fusion gene, which may open the door in the future is. Development of cancer therapy that specifically destroys tumors without affecting healthy cells. Publishes in Nature communication.

Fusion genes are an unusual result of misalignment of DNA fragments that come from two different genes, a phenomenon that occurs by accident during the process of cell division. If the cell cannot benefit from this error, it will die and the fusion gene will be eliminated. But when the error results in reproduction or survival gain, the carrier cells will multiply and the fusion genes and proteins they encode thus become a tumor formation triggering event. “Many of the chromosomal rearrangements and fusion genes they produce are at the core of childhood sarcomas and leukemias,” explains Sandra Rodriguez-Pereles, the lead co-author of the study published by CNIO. Fusion genes are found, among others, in prostate, breast, lung, and brain tumors: in total, up to 20% of all cancers.

Because they only exist in tumor cells, fusion genes are of great interest among the scientific community because they are highly specific therapeutic targets, and attacking them only affects the tumor and has no effect on healthy cells.

And that’s where CRISPR technology comes into practice. With this technique, researchers can target specific sequences of the genome, such as cutting and pasting pieces of DNA using molecular scissors and thus modifying the genome in a controlled manner. In a study by the CNIO team, researchers worked with cell lines and mouse models of Ewing’s sarcoma and chronic myeloid leukemia, in which they managed to eliminate tumor cells by cutting the tumor-causing fusion genes.

Tumor cell repairs itself … and destroys itself

This is the first time that CRISPR has been successfully applied for selective elimination of fusion genes in tumor cells. Earlier strategies by other research teams were based on modifying the junction between two genes involved in fusion to initiate a DNA sequence that induces cell death. The problem is that the introduction of foreign sequences has proved to be very ineffective in eliminating tumors.

CNIO researchers used a completely different approach to induce tumor cells to destroy themselves. “Our strategy was to make two cuts in the non-coding regions of the gene, which are located at both ends of the fusion gene,” explains the paper’s co-author Raul Torres-Ruiz. “In this way, in an attempt to fix those breaks on their own, the cell will join the cut loops, resulting in complete elimination of the fusion gene located in the middle”. Since this gene is essential for cell survival, this repair automatically causes tumor cell death.

“Our next step will be to conduct more studies to analyze the safety and efficiency of our approach,” said Rodriguez-Perels. “These steps are necessary to know whether our approach can be translated into potential clinical treatment in the future. In addition, we will study whether our strategy, which we have already identified, as Ewing’s sarcoma and chronic myeloid Seen to work in leukemia, is also effective in others. The type of cancer caused by the fusion gene and for which there are currently no effective treatments, “he concludes.”

Uncovering a signaling pathway disruption that sensitizes tumor cells to a particular drug

more information:
M. Martinez-Laag et al., In vivo targets fusion oncogenes for selective elimination of CRISPR / Cas9 cancer cells, Nature communication (2020). DOI: 10.1038 / s41467-020-18875-x

Provided by the Spanish National Cancer Research Center

Quotes: The team reprimanded the CRISPR system to eliminate tumor cells without affecting healthy cells (2020, 8 October). Retrieved 9 October 2020 from Html

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