by Braulio Valdebenito-Maturana

Example of a transposable element following cancer development on spatially resolved data. In green the normal epithelium, in brown the serrated lesion, and in red the tumor region. The arrow depicts the pathological transformation between these regions. Credit: Valdebenito-Maturana B. Scientific Reports (2024). DOI: 10.1038/s41598-024-73744-7

Gastric cancer (GC) is a lethal malignancy with worldwide occurrence, and is considered endemic in eastern Asian, eastern European and South American countries. Indeed, in my home country, Chile, GC is the leading cause of cancer death in men.

The main problem with GC is that it is often detected at advanced stages, when it can have a survival rate of less than 10%. By contrast, the survival rate of early GC cases can be as high as 90%. This has prompted the need for novel methods for early and timely detection.

Transposable elements (TEs), the so-called "jumping genes," are seldom studied due to computational difficulties. Nonetheless, in recent years, there has been an increase in studies focused on the role of TEs in different types of cancer. However, their impact has not been previously studied for GC.

In my recent work, now published in Scientific Reports, I discovered that TE expression is a hallmark of GC, and that their activity could be linked with the acquisition of malignant or "tumoral" status.

A primer on 'jumping genes'

The human genome is about 3 billion bases long, yet only about 1% of it corresponds to protein-coding genes. By stark contrast, close to 50% of the human genome corresponds to transposable elements, which are highly repetitive elements due to their "jumping" nature: TEs have the ability to replicate and move themselves in the genome.

Originally, they were labeled "junk DNA" because of their apparent parasitic and selfish nature to just create more copies. Barbara McClintock pioneered the work revealing that TEs play an important role in controlling gene expression, and for this discovery, she was awarded a Nobel prize in 1983.

Today, it is well known that TEs can be involved in gene regulation in healthy and disease conditions, as I and many other groups have reported. This has been possible thanks to the development of computational tools for their study, an area to which I and several laboratories have contributed.

Results from trajectory inference analysis showing a transposable element that is expressed on the malignant cell lineages. Left, the trajectory colored by malignancy as measured by inferCNV scores, and right, expression of a transposable element across the trajectory. Credit: Valdebenito-Maturana B. Scientific Reports (2024). DOI: 10.1038/s41598-024-73744-7

Transposable elements in gastric cancer

In my study, I first leveraged single-cell RNA sequencing data to reconstruct the cell evolution from normal toward malignant status, and assessed if TE activation is associated with those "tumoral" cell lineages. Afterward, to validate and further characterize that TE activation is a hallmark of GC, I also assessed their activation in spatially resolved RNA sequencing data.

Although the computational modeling of cell evolution, "trajectory inference," is an area with much development, it has not been widely applied to the study of cancer. By combining that approach with my expertise in TEs, I characterized GC cell evolution, and found that 111 of these "jumping genes" are activated in the malignant cell lineages.

On the other hand, with spatially resolved data, we already see expression in the tissue as it is. Here, I found that TEs are activated in both the tumor regions and their surroundings (the so-called tumor microenvironment). In some cases, I even found that TEs follow the transition from normal toward the tumor regions, further supporting the findings from the first part of the study

What's next?

These results are quite interesting in the sense that we can see that, similar to other cancer types, TE expression also occurs in gastric cancer. In addition to that, this is the first study reporting that these elements become active in early stages of the disease. This would point to these "jumping genes" being novel biomarkers for its timely detection.

The next step for this research is experimentally validating these findings, and if we find out that these elements are consistently detected in early stages, we might be on our way to find novel treatments for and ways to stop gastric cancer.

This story is part of Science X Dialog, where researchers can report findings from their published research articles. Visit this page for information about Science X Dialog and how to participate.

More information: Braulio Valdebenito-Maturana, The spatial and cellular portrait of transposable element expression during gastric cancer, Scientific Reports (2024). DOI: 10.1038/s41598-024-73744-7

Journal information: Scientific Reports 

Braulio Valdebenito-Maturana is a bioinformatics scientist, focused in developing and applying computational methods to enhance our understanding of the molecular mechanisms of gastric cancer.