Scientists have developed a new technique to quantify gene splicing and create a much clearer picture of how tumors rewire genetic instructions to fuel their growth. A study published today in Nature Communications reports the application of this novel method to 10,000 tumor biopsies, revealing about 120 new therapeutic targets that are active across a wide range of cancer types.
Gene splicing is a cellular process that governs the editing of messenger RNA, allowing for a single gene to encode for multiple proteins. Cancer cells are known to hijack splicing to produce protein variants that help them grow, evade the immune system, or resist treatment.
Researchers often study gene splicing by looking at the splicing factors the performs the edits. However, this creates an incomplete picture as the splicing process is also affected by other factors such as chemical modifications or subcellular location. The new method, developed in collaboration between the Centre for Genomic Regulation in Barcelona and Columbia University, circumvents these limitations by directly looking at the edits rather than the editors.
“Instead of counting parts, our approach has been to understand behavior, which has unlocked a new way of navigating a tumor’s chaotic biology,” said Miquel Anglada Girotto, PhD, postdoctoral researcher at the Centre for Genomic Regulation and lead author of the study. “It’s early, but it gives us a much clearer map of where to look to find new ways of targeting the disease.”
Anglada Girotto and colleagues adapted an existing method known as VIPER (virtual inference of protein activity by enriched regulon), which is used to estimate how much of each possible protein variant is expressed from a single gene. Since the method is applied on RNA sequencing data, it can be easily applied to existing datasets to reveal the underlying patterns of gene splicing without the need for additional tests or experiments.
The team then applied this new method to 10,000 tumor biopsies spanning 14 cancer types. They were obtained from The Cancer Genome Atlas (TCGA), a catalogue of genomic alterations where each tumor sample is paired with a healthy tissue sample. Results revealed two broad gene splicing programs found across all cancer types, suggesting that different cancers may share common splicing strategies.
Around 120 molecules were found to be involved in tipping these splicing programs towards cancer phenotypes, offering novel therapeutic targets across multiple types of cancer. One of the strongest candidates was FUS, a gene known to be involved in the development of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. Although mutations in this gene have previously been found to be implicated in sarcoma tumors, it has not been widely studied in the context of cancer research.
Down the road, this method could have applications beyond cancer research, as it could provide brand new insights into a wide range of conditions where gene splicing plays a major role. “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,” said Anglada Girotto.
