Cancer is caused by faulty genes, but what also shapes a cancer cell’s behaviour is how a gene’s instructions are trimmed and rearranged before they are turned into the proteins that keep a cell alive.

A study published today in Nature Communications reveals a new way of measuring that editing process, known as splicing, directly.

It is the first time scientists have been able to get a clear view of how tumours systematically rewire their genetic instructions to aid growth and survival, and it may point toward new ways of controlling the disease.

As a proof of concept, the researchers used the method on solid tumour biopsies.

They found around 120 potential new therapeutic targets, molecules that might one day be dialled up or down to restore balance in the cell’s editing machinery.

“Instead of counting parts, our approach has been to understand behaviour, which has unlocked a new way of navigating a tumour’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,” says Dr. Miquel Anglada Girotto, first author of the study and postdoctoral researcher at the Centre for Genomic Regulation in Barcelona.

Measuring the edits instead of the editors

Inside every cell, genetic instructions are first copied into temporary messages.

Before those messages are used, the cell cuts out some segments and stitches the rest together.

This editing step allows a single gene to create different messages which produce different proteins, a necessary feature for complex life.

Almost all cancers hijack cellular splicing, altering how messages are cut and pasted.

Tumours do this to produce protein variants that help them grow faster, hide from the immune system or resist treatment.

To understand this process scientists usually measure the molecules that perform the editing, also known as splicing factors.

However, these cellular editors can be controlled in many hidden ways, with their activity seemingly appearing unchanged even while the proteins themselves are being destroyed, chemically modified or moved to different parts of the cell.

The result is often a confusing picture which hampers progress in the search for new ways to control the disease.

A team at the Centre for Genomic Regulation in Barcelona and Columbia University addressed this problem by turning the logic around and measuring the edits themselves, rather than the editors.

The researchers adapted an existing technology called VIPER to measure which segments of a gene’s message are kept, and which are removed.

These patterns act like fingerprints on genetic messages, revealing which editing forces were truly active, regardless of how the editors are regulated.

The technique can be used on RNA sequencing data, which is widely available.

It means the technique can be applied to thousands of existing samples without the need for new experiments.

Two hidden cancer programmes

The researchers applied VIPER to around 10,000 tumour biopsies from 14 different cancer types in The Cancer Genome Atlas, a publicly available database.

Each biopsy is paired with matched healthy tissue samples for comparison.

They found two broad cellular editing programmes which repeatedly appeared across all types of cancer.

One programme behaved like an accelerator, becoming more active in tumours and aligning with poorer patient outcomes.

The other behaved like a brake, losing strength in cancer and aligning with better survival.

The discovery suggests that cancers, despite their diversity, share common cellular editing strategies that have been hidden from view by research looking at genes alone.

When the researchers looked for biological features that help tip a cell’s editing balance towards cancer, they found around one hundred candidates.

Among the most prominent was a gene called FUS, better known for its role in neurological conditions.

Although not widely studied in cancer research, its strong predictive signal suggests it may deserve closer attention.

The implications extend beyond cancer.

Because the technique focuses on the outcome of genetic editing rather than the specific cause, it could be applied to many diseases in which cells alter how they assemble their instructions.

“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,” concludes Dr. Anglada Girotto.

The work was led by Dr. Anglada Girotto alongside Dr. Luis Serrano and Dr. Samuel Miravet-Verde at the CRG.

The study builds on analytical tools originally developed by Andrea Califano and colleagues at Columbia University.

The research was supported by European Research Council, the Spanish Ministry of Science and Innovation and the Generalitat de Catalunya.

Source: Center for Genomic Regulation