Early genetic change allows lung cancer to evolve

Every cell in the human body contains a copy of our genome, the unique genetic instructions made of DNA that make us who we are. In healthy human cells, the genome usually comprises 23 pairs of chromosomes (bundles of DNA).

Cancer cells, however, can have whole or parts of chromosomes that have been duplicated or deleted, known as ‘chromosomal instability’. They can also double their entire set of chromosomes when replicating, giving them a back-up copy of their genome.

These changes help them to adapt to their environment, hide from the immune system and become harder to hit with targeted treatments.

In new research published in Nature Cell Biology, scientists studied non-small cell lung cancer (NSCLC) samples from the Cancer Research UK-funded TRACERx study, to investigate which genetic changes make chromosomal instability and whole genome doubling more likely.

They identified that a gene called FAT1 was mutated in lung cancer cells with unstable chromosomes before they doubled their genomes.

Using specialised imaging techniques, the team showed that cells with a complete loss of FAT1 couldn’t divide to produce two new cells in the normal way. Instead, this loss led to the new cells sharing an uneven number of chromosomes, or in some cases their DNA was attached through a ‘chromosomal bridge’, meaning their genomes were doubled within a larger, unstable cell.

When FAT1 and another gene involved in cell size regulation called YAP1 were removed, the cancer cells no longer doubled their genomes. This suggests that drugs that block YAP1, which are currently being tested, could be particularly effective against cells with high levels of chromosomal instability.

Finally, the researchers removed FAT1 in lung cancer cells that are normally sensitive to a cancer drug called osimertinib, observing that more of these cells survived. They believe that FAT1 loss could help cells adapt and become more resistant to treatment.

Professor Charles Swanton, senior author of the study from UCL Cancer Institute and the Francis Crick Institute, and Chief Investigator of the Cancer Research UK TRACERx study, said: “Lung cancer is particularly hard to treat and can spread easily, but we don’t yet have a full picture for why this is the case.

“We’ve now shown that losing FAT1 gives these cells an evolutionary advantage, as they can pick up more genetic mutations but also retain a back-up manual by doubling their genome. More research is needed, but this suggests that FAT1 mutations in people with early-stage lung cancer could be a predictive marker that their cancer is more likely to spread or develop resistance.”

Wei-Ting Lu, a postdoctoral project research scientist at the Crick and first author of the study, said: “Whole genome doubling is a key event which drives lung cancer to evolve, but the genes behind this haven’t been well-characterised. We’ve now shown that FAT1 mutations kick off the process early in cancer development. Advanced imaging techniques have allowed us to see close-up how cells fail to replicate properly when FAT1 is removed.”

The research team also included Barts Cancer Institute, Queen Mary University of London and the Danish Cancer Society Research Centre. The TRACERx Consortium is funded by Cancer Research UK.

Dr Nnenna Kanu, Chief Scientific Officer at the UCL Lung Cancer Centre of Excellence, said: “We had a limited understanding of what fuels the diversity of chromosome numbers and structures we see in lung tumours. Now, we have had the unique opportunity to coordinate experimental biology with genomics and clinical observations to elucidate a key role for FAT1 in driving genome instability. We observed that many tumours make multiple efforts to lose FAT1 in an attempt to speed up their evolution.”

Links

• Professor Charles Swanton's academic profile
• Dr Nnenna Kanu's academic profile
• UCL Cancer Institute
• UCL Faculty of Medical Sciences
• The Francis Crick Institute

Image

• Credit: Artur Plawgo on iStock.

Media contact 

Dr Matt Midgley

E: m.midgley [at] ucl.ac.uk