Work led by Dr Anna Rose and DPhil student Tomas Goncalves has unpicked a key DNA interaction that leads cells to become cancerous via a particular pathway that causes up to 80% of the cancers affecting children and young people.
ALT cancers, as they are known, all have a commonality: the cancer cells in this group of cancers all have elongated telomeres achieved via process called Alternative Lengthening of Telomeres (ALT). Such elongated telomeres are a key feature of cancer cells – elongating their telomeres (the protective end cap on chromosomes) allow cancer cells to divide endlessly, escaping the normal programme of cell death that regulates other cells when they are no longer useful to the body.
Researchers also know that the loss of the ATRX gene is a central genetic event which leads to the development of ALT cancers, but previous work has also shown that this alone is not enough to transform a normal cell into a cancerous one- a second factor is required. The central genetic event in the development of ALT cancers is the loss of the ATRX gene. However, it has been shown that loss of ATRX is not sufficient to transform a normal cell into a cancerous cell -- a second factor is required.
Now a study published in Nucleic Acids Research has found that excessive ‘trapping’ of DNA-interacting proteins onto the DNA is likely to be the second causative factor driving development of the ALT pathway. In the study, the research team (which included researchers from the Department of Oncology, with Dr David Clynes as senior study author), researchers treated cells with several drugs ('trapping agents), which cause damage by sticking proteins tightly to the DNA strand, causing a physical blockade. These drugs are used clinically as chemotherapy – because DNA damaging agents are highly effective at killing fast dividing cells, such as cancer cells. However, DNA damage is also the initial cause of cancer and so the same drugs can be used to study the origins of the disease.
Dr Rose said “We found that treating cells without the ATRX gene with these trapping agents set off the ALT pathway, but did not affect ATRX-expressing cells.” (the main image's top row shows normal cells, while the bottom row shows ATRX deficient ALT cancer cells. The green dots in the middle panel shows trapped TOP1 protens - the bottom row shows a massive increase in these in ALT cells).
Dr Rose added “We also found that compared to non-ALT cancer cells, ALT cancer cells from patients had higher levels of trapped proteins. Our ongoing work is exploring why these cells have accumulated trapped proteins – we hope that these insights into the underpinning molecular mechanisms will give rise to new therapeutic approaches."