An innovative technique allows to detect body mutations triggered by oncological diseases

MIT Technology Review Italy

In their latest work, published in Cell, MIT’s Jonathan Weissman and others report the complete history of the behavior of lung cancer cells from the first activation of cancer mutations to the final stage in which cells become aggressive and metastatic. Researchers want to understand the evolution of these characteristics in order to prevent and treat deadly cancers, why when cancer is discovered in a patient, it typically has been around for years or even decades, and key moments in the different steps have gone unnoticed.

Their method uses CRISPR technology to embed each cell with an inheritable and evolutionary DNA barcode. Starting from the fact that every time a cell divides, its barcode is slightly modified, the researchers examined the descendants of the original cells to reconstruct the family tree of each individual cell, noting how and when the cells developed traits. important.

In order to monitor cancer from an early stage, the researchers simultaneously triggered disease-causing mutations in cells, starting to record the cellular pathway.. The mice were exposed to a cancerous mutation in the Kras gene, turning off the tumor suppressor gene Trp53 in the cells. The evolution of lung cancer has been very similar to that of humans, in the sense that the progression of the disease occurs over a long period in its native environment.

The researchers let the cancer cells evolve for several months before examining them. They then used a computational approach developed in their previous work to reconstruct cell family trees from modified DNA barcodes. They also measured gene expression in cells using RNA sequencing to characterize the status of each individual cell. With this information, they began to piece together how this type of lung cancer becomes aggressive and metastatic.

The results showed significant diversity between cell subpopulations within the same tumor. In this model, cancer cells mainly evolved through heritable changes in their gene expression, rather than through genetic mutations. Some subpopulations have taken dominance over time. In the researchers’ opinion, genes identified as commonly expressed in these cells could be a therapeutic target.

Furthermore, it was found that metastases originated only from these dominant cell groups and exclusively at the end of their evolution: a behavior different from other tumors, in which cells can acquire the ability to metastasize at the beginning of their evolution. This finding could be important for anti-cancer therapies because if researchers know which types of cancer develop the ability to metastasize in this gradual way, they can design interventions to stop the progression.

Researchers also uncovered important details of the evolutionary paths cancer subpopulations take to develop and become aggressive.. Cells evolve through different states, defined by the key characteristics the cell has at that time. In this cancer model, researchers found that cells in a tumor initially diversified rapidly, moving from one state to another. However, once a subpopulation has reached a dominant state, it has never moved from this position.

Furthermore, the ultimately dominant cells appeared to follow one of two distinct pathways through different cell states. One of these pathways could lead to further progression that allowed tumors to enter aggressive ‘mesenchymal’ cellular states, which are linked to metastases.

After the researchers thoroughly mapped the developmental pathways of the cancer cells, they wondered how these pathways would be affected if the cells underwent further cancer-related mutations, then turned off one of the two additional cancer suppressors. One of these influenced the state in which the cells stabilized, while the other caused the cells to follow a completely positive evolutionary path.

The strength of this study is that it allows us to study the evolution of tumors in fine-grained detail“Says one of the authors Matthew Jones. “Whenever there is a shift from mass analysis to single-cell analysis in a technology, the scope of biological insights and possible therapeutic developments is greatly expanded.”

Image: Pixabay, Qimono

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