The alternative RNA splicing is like a film editor that cuts and reorganizes scenes of the same images to create different versions of a film. When selecting what scenes conserve and which ones leave aside, the editor can produce a drama, a comedy or even a thriller, all of the same raw material. Similarly, the cells splic RNA in different ways to produce a variety of single gene proteins, adjusting their function based on the need. However, when cancer rewrites the script, this process goes wrong, feeding tumor growth and survival.
In a recent study reported in the February 15 edition of Nature communicationsJackson Laboratory scientists (Jax) and UConn Health not only show how cancer kidnaps this splicing and strictly regulated reorganization of RNA, but also introduces a potential therapeutic strategy that could slow or even reduce aggressive and difficult tumors. This discovery could transform how we treat aggressive cancers, such as triple negative breast cancer and certain brain tumors, where current treatment options are limited.
In the heart of this work, directed by Olga Anczuków, a professor associated at Jax and leader of co-program programs at the Jax Cancer Center designated by NCI, they are small genetic elements called poison exons, the “off switch” of nature for protein production. When these exons are included in an RNA message, they trigger their destruction before a protein can be made, avoiding harmful cell activity. In healthy cells, poison exons regulate key protein levels, keeping genetic machinery under control. But in cancer, this security mechanism often fails.
Anczuków and his team, including Nathan Leclair, a student graduated from MD/Doctorate at Uconn Health and the Jackson laboratory who led the investigation, and Mattia Brugioolo, a staff researcher who contributed his experience, discovered that cancer cells suppressed exon’s activity in a gene Tra2β. As such, levels of Tra2β Proteins increase within cancer cells, causing tumor proliferation.
In addition, the team found a correlation between poison exons levels and patient results. “We have demonstrated for the first time that the low levels of inclusion of former poison in the Tra2β Genes are associated with bad results in many different types of cancer, and especially in aggressive and difficult to treat cancers, “said Anczuków. These include breast cancer, brain tumors, ovarian cancers, leather cancers, leukemia and colorectal cancers, Anczuków explained.
Anczuków, Leclair and Brugiolo then saw if they could increase the inclusion of the exon of the poison in the Tra2β gene and reactive the killing switch. They found their response in Oligonucleotides Antisentido (Asos): Synthetic RNA fragments that can be designed to increase the inclusion of exon poison specifically. When it was introduced into cancer cells, ASO effectively turned the genetic switch, restoring the natural capacity of the body to degrade excess Tra2β RNA and inhibit tumor progression.
“We discover that ASO can quickly boost the inclusion of former poison, essentially deceiving the cancerous cell so that they do not achieve their own growth signs,” Leclair said. “These poison exons function as a rheostate, quickly adjusting protein levels, and that could make Asos a highly precise and effective therapy for aggressive cancers.”
Interestingly, when the researchers completely eliminated Tra2β The proteins that use the edition of the CRISPR gene, the tumors continued to grow, which suggests that addressing RNA instead of the protein could be a more effective approach. “This tells us that the RNA that contains poisoner in poison should not only silence Tra2β“Anczuków explained.” It probably kidnaps other RNA binding proteins, creating an even more toxic environment for cancer cells. “
Other studies will refine ASO -based therapies and explore their supply to tumors. However, preliminary data suggests that ASO are highly specific and do not interfere with normal cell function, which makes them promising candidates for future cancer treatments. This research was supported by the National Health Institutes and the Jax Cancer Center designated by NCI.