Modified VIPER Approach Accurately Captures Splicing Factor Activity

A study published in Nature Communications describes a technique that directly measures RNA splicing to reveal how cancer cells modify gene instructions for growth and survival. By focusing on the editing process where cells cut and rearrange RNA messages before protein production, the method provides the first detailed view of these alterations in tumors. Testing on solid tumour biopsies uncovered around 120 potential therapeutic targets to potentially restore normal cellular editing.

Genes produce RNA messages that cells splice by removing certain segments and joining others, enabling a single gene to create diverse proteins. Cancers commonly hijack this splicing to generate proteins that promote faster growth, immune evasion, or drug resistance. Traditional studies examined splicing factors—the molecules executing these edits—but missed cases where factors remained unchanged in quantity yet were chemically altered, relocated, or degraded. 

Researchers from the Centre for Genomic Regulation in Barcelona and Columbia University instead analyzed the edits directly. They modified VIPER, an established technology, to identify which RNA segments stay and which get removed. These patterns function as fingerprints of active splicing activity, regardless of how editing molecules are regulated. Compatible with routine RNA sequencing data, the approach allows examination of thousands of existing samples without additional experiments.

Analysis of roughly 10,000 tumor biopsies from 14 cancer types in The Cancer Genome Atlas—each matched with healthy tissue—revealed two consistent splicing programs. One program intensifies in tumors and links to worse patient survival, while the other fades in cancer and correlates with improved outcomes. These findings expose shared editing mechanisms across varied cancers that gene-centric research overlooked.

According to first author Miquel Anglada Girotto, “Instead of counting parts, our approach has been to understand behavior, which has unlocked a new way of navigating a tumor’s chaotic biology. It’s early, but it gives us a much clearer map of where to look for to find new ways of targeting the disease.”

The study pinpointed about 100 factors driving these splicing changes, including FUS—a gene known for neurological roles that displayed strong predictive signals in cancer. Since the technique targets editing results rather than specific triggers, Dr. Anglada Girotto suggests wider applications: “We started with cancer because the data was available, but the approach could work for any disease where cells change how they edit their messages, including neurological disorders or immune diseases.”