Rewriting the Script: Targeting Alternative RNA Splicing to Treat Cancer

By deciding which sequences to keep and which to cut, the editor can create a drama, a comedy, or even a thriller from the same raw material.

California [US], March 16 : Alternative RNA splicing is similar to a movie editor cutting and rearranging scenes from the same video to produce distinct versions of a film. By deciding which sequences to keep and which to cut, the editor can create a drama, a comedy, or even a thriller from the same raw material.

Similarly, cells splice RNA in various ways to make a wide range of proteins from a single gene, fine-tuning their activity to meet specific needs. However, when cancer rewrites the script, this process is disrupted, promoting tumor growth and survival.

In a recent study, scientists from The Jackson Laboratory (JAX) and UConn Health not only show how cancer hijacks this tightly regulated splicing and rearranging of RNA but also introduce a potential therapeutic strategy that could slow or even shrink aggressive and hard-to-treat 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.

At the heart of this work, led by Olga Anczukow, an associate professor at JAX and co-program leader at the NCI-designated JAX Cancer Center, are tiny genetic elements called poison exons, nature's own "off switch" for protein production. When these exons are included in an RNA message, they trigger its destruction before a protein can be madepreventing harmful cellular activity. In healthy cells, poison exons regulate the levels of key proteins, keeping the genetic machinery in check. But in cancer, this safety mechanism often fails.

Anczukow and her team, including Nathan Leclair, an MD/PhD graduate student at UConn Health and The Jackson Laboratory who spearheaded the research, and Mattia Brugiolo, a staff researcher who contributed his expertise, discovered that cancer cells suppress poison exon activity in a critical gene called TRA2b. As such, levels of TRA2b protein increase inside cancer cells, causing tumor proliferation.

Furthermore, the team found a correlation between levels of poison exons and patient outcomes. "We've shown for the first time that low levels of poison exon inclusion in the TRA2b gene are associated with poor outcomes in many different cancer types, and especially in aggressive and difficult-to-treat cancers," said Anczukow. These include breast cancer, brain tumors, ovarian cancers, skin cancers, leukemias, and colorectal cancers, Anczukow explained.

Anczukow, Leclair, and Brugiolo then went on to see if they could increase the inclusion of the poison exon in the TRA2b gene and reactivate the kill switch. They found their answer in antisense oligonucleotides (ASOs)synthetic RNA fragments that can be designed to increase poison exon inclusion in specific ways. When introduced into cancer cells, ASOs effectively flipped the genetic switch, restoring the body's natural ability to degrade excess TRA2b RNA and inhibit tumor progression.

"We found that ASOs can rapidly boost poison exon inclusion, essentially tricking the cancer cell into turning off its own growth signals," said Leclair. "These poison exons work like a rheostat, quickly adjusting protein levelsand that could make ASOs a highly precise and effective therapy for aggressive cancers."

Interestingly, when researchers completely removed TRA2b proteins using CRISPR gene editing, tumors continued to growsuggesting that targeting the RNA rather than the protein could be a more effective approach. "This tells us that poison-exon-containing RNA doesn't just silence TRA2b," explained Anczukow. "It likely sequesters other RNA-binding proteins, creating an even more toxic environment for cancer cells."

Further studies will refine ASO-based therapies and explore their delivery to tumors. However, preliminary data suggest that ASOs are highly specific and do not interfere with normal cellular function, making them promising candidates for future cancer treatments.

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