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Tumour cells can speed up genetic mutations to resist therapies

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Coloured scanning electron micrograph (SEM) of a cancer cell from the human colon (large intestine), also known as colorectal cancer. Credit: Steve Gschmeissner/Spl/Getty Images.

Metastases and resistance to therapy are the main cause of cancer recurrence. In some cases patient relapse is fast, due to genetic mutations already detected in the tumour mass before any treatment. In other cases, however, the tumour reappears years after therapy, and clinicians do not know how or why. A step toward answering these questions has emerged from a study by a team led by Marco Cosentino Lagomarsino, from IFOM and Università di Milano, and Alberto Bardelli, from the Candiolo Cancer Institute and Università di Torino. The study, published in Nature Genetics, is an elegant combination of quantitative experiments and mathematical modelling1.

As they set out to investigate the behaviour of cancer cells, the authors were inspired by the pioneering experiment on virus resistance in bacteria by Salvador Luria and Max Delbrück in the 1940s2, and designed their experiments on colon cancer cell lines (CRCs) in a similar way.

“We knew from our previous work that human CRCs treated with certain therapies display an up-regulation of error-prone DNA polymerases, that are enzymes involved in DNA replication and a reduction in their ability to repair DNA damage,” explains Cosentino Lagomarsino. “Like bacteria, cancer cells can adapt to therapeutic pressure by enhancing their mutability”. Indeed, when exposed to stress induced by molecularly targeted therapies, cancer cells initiate a response known as “adaptive mutability”, very similar to bacteria’s response to antibiotics, which is the basis of antibiotic resistance. Now, the authors have characterized and quantified this temporary increase in the cells’ ability to mutate.

The experiments involved several weeks of controlled culture growth and death in order to build a statistic from thousands of wells where the cells were cultivated. The scientists first measured how the growth parameters of CRCs were affected by drug treatment. Then, they deployed a two-step fluctuation test (the experimental technique originally developed by Luria and Delbruck) to assess the rate of phenotypic mutations. This assay discriminates pre-existing resistant clones from newly developed ones, allowing to quantify both spontaneous and drug-induced mutation rates.

This work shows that cancer cells have a trump card which they use to get around the action of therapies, often leading to treatment failure and disease recurrence. However, it also reveals new weak points of the same cancer cells. Future experiments could focus on the identification of key proteins that modulate the mutation ability in cancer cells, possibly allowing to block them with drugs and prevent tumour relapse.

doi: https://doi.org/10.1038/d43978-022-00096-z

References

  1. Russo, M., Pompei, S., Sogari, A. et al. Nat Genet 54, 976–984 (2022).

    PubMed  Article  Google Scholar 

  2. S. E. Luria, M. Delbrück, Genetics, 28, 6, (1943).

    Article  Google Scholar 

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