Cells utilize genetic instructions to produce the proteins needed for the body to function. In cancer, these instructions can be altered before being translated into proteins, changing how cells behave. A latest study details how these changes can be directly measured, offering a clearer picture of how tumors reorganize their genetic activity.
Cancer arises from faulty genes, but the behavior of a tumor cell is similarly influenced by how genetic instructions are modified before they become the proteins essential for cell life.
Research published Thursday, August 14, 2024, in the journal Nature Communications, describes a method for directly measuring this genetic editing process, known as splicing.
The research provides, for the first time, a clear view of how tumors systematically reorganize these instructions to support the growth and survival of cancer cells. Understanding these mechanisms is a crucial step toward developing more targeted cancer therapies.
To validate the method, researchers analyzed biopsies from solid tumors and identified approximately 120 potential therapeutic targets – molecules that could be regulated in the future to restore balance to the genetic editing mechanisms within cells.
The study was conducted by a team from the Center for Genomic Regulation (CRG) in Barcelona, in collaboration with Columbia University.
Inside each cell, genetic instructions are first copied by RNA into temporary messages. Before these messages are used to produce proteins, the cell removes certain segments and combines the remaining ones. This editing process allows a single gene to generate different messages, which can produce distinct proteins – a mechanism essential for the functioning of complex organisms.
Most types of cancer modify the splicing process, changing how these messages are cut and reassembled.
Tumors use this strategy to produce protein variants that can promote rapid cancer cell growth, help evade the immune system, or contribute to treatment resistance.
Typically, researchers analyze the molecules that carry out this editing process, known as splicing factors. However, the activity of these molecules can be influenced by mechanisms that are not easily observed.
For example, proteins can be degraded, chemically modified, or mutated in other areas of the cell without their apparent levels changing. This can create an incomplete picture of how the genetic editing process is working.
To overcome this limitation, the research team adopted a different approach: instead of measuring the factors that perform the editing, they analyzed the changes produced directly in the genetic messages.
Researchers adapted an existing technology, called VIPER, to identify which segments of genetic messages are retained and which are eliminated.
The resulting patterns function as a fingerprint of the genetic messages and show which editing mechanisms have been active, regardless of how the involved molecules are regulated.
The method can be applied to data obtained through RNA sequencing, a type of genetic analysis widely used. This means the technique can be used to analyze thousands of existing samples without the require for additional experiments.
Researchers applied the VIPER method to approximately 10,000 tumor biopsies from 14 different types of cancer, using data from The Cancer Genome Atlas, a public database.
For each tumor sample, they also analyzed matching healthy tissue samples for comparison.
The analysis identified two major programs of cellular editing, repeatedly present in all the cancer types studied.
One program functions as an accelerator: it becomes more active in tumors and is associated with a less favorable outcome for patients.
The other program functions as a braking mechanism: its activity decreases in cancer and is associated with better survival.
The discovery suggests that, despite their diversity, different types of cancer may employ common strategies to reorganize genetic editing processes – strategies that have remained difficult to observe in studies focused exclusively on genes.
When analyzing the biological factors that may influence the balance of these cellular editing programs, researchers identified approximately one hundred candidates.
Among the most prominent was the FUS gene, best known for its role in some neurological conditions. Although it has not been widely investigated in cancer research, the strong signal identified in the analysis suggests that this gene could be a relevant subject for further study.
According to the authors, the method could also have applications in other areas of medicine.
Due to the fact that the technique analyzes the result of the genetic editing process, not the specific cause, it could be used to study diseases in which cells modify how they assemble their genetic instructions. “We started with cancer because data were available, but this approach could work for any disease in which cells modify how they edit their genetic messages, including neurological disorders or immune system diseases,” said Dr. Miquel Anglada Girotto, the study’s first author and a postdoctoral researcher at CRG, in a statement.
