Alternative RNA splicing is analogous to a movie editor editing and rearranging sections from a single video to create different versions of a film. By determining which scenes to keep and which to eliminate, the editor can transform the same raw material into a drama, a comedy, or even a thriller.
Similarly, cells splice RNA in a variety of ways to produce a diverse array of proteins from a single gene, fine-tuning their function to satisfy specific requirements. However, when cancer alters the script, this mechanism is disturbed, increasing 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 tumours. This discovery could transform how we treat aggressive cancers, such as triple-negative breast cancer and certain brain tumours, 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 made-preventing 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 tumour 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 tumours, 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 tumour 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 levels-and that could make ASOs a highly precise and effective therapy for aggressive cancers."
Interestingly, when researchers completely removed TRA2b proteins using CRISPR gene editing, tumours continued to grow-suggesting 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 tumours. 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. |
