For the first time, a new study published today in the journal PNAS demonstrates that the telomeres, the cell’s anti-aging structures, can determine the amount of damage that a cancer cell can tolerate before it stops dividing and dying. These findings bring up new avenues for cancer treatment.

For the first time, a new study led by Claus M. Azzalin, head of the group at the Instituto de Medicina Molecular Joo Lobo Antunes- iMM, and published today in the journal Proceedings of the National Academy of Sciences (PNAS) demonstrates that the telomeres, the cell’s anti-aging structures, can determine the amount of damage that a cancer cell can tolerate before it stops dividing and dying. These findings bring up new avenues for cancer treatment.

Telomeres are chromosomal ends that shorten with each cell division, acting as a cell ageing clock.

With the help of telomerase, a molecule that stops chromosome ends from getting shorter, most cancer cells are able to stop this ageing clock.

However, ALT cells, a form of cancer cells that can maintain their telomeres without the help of telomerase and are notably resistant to standard chemotherapies, make up around 10% of human malignancies.

The ability of ALT cells to maintain controlled levels of DNA damage in their telomeres at each cell division is necessary for their telomeres to be prolonged, which enables them to divide endlessly.

Now, Bruno Silva and Claus M. Azzalin of iMM have found that TERRA, an RNA molecule made from the telomeres, is the cause of this damage.

“When the levels of TERRA are increased,” as explained by first author Bruno Silva, “the damage at telomeres also increases and this becomes so heavy that even a cancer cell that usually is more resistant, is not able to multiply anymore.” 

Earlier, they showed “that this molecule – TERRA – has an important role in this process of damaging the DNA”.

Now, they have “figured out what molecular mechanism happens inside these ALT cells”.

While TERRA is naturally more prevalent in ALT cells than in normal cells, where it is only found at very low quantities and its physiological function is still completely unclear.

However, the research team noticed an accumulation of damage in the DNA of the telomeres when they employed molecular tools to further boost the quantities of TERRA inside the ALT cancer cells.

“This manipulation has two outputs for the ALT cancer cell,” explains Bruno Silva, “first, the maintenance of the damaged telomere is activated and second, to restore this damage, other telomeres are used and lost. The consequence for the cancer cell is catastrophic! The cell cannot take multiple damaged telomeres and stops dividing.”

Claus M. Azzalin comments on the significance of these findings by saying, “this makes TERRA a uniquely versatile target for therapy. 

“By decreasing its levels,” the author adds, “we can block telomere maintenance, as we have shown before, while by increasing TERRA levels, we can rise the damage to levels that are not sustainable even for a cancer cell, eventually leading to cell death”. 

Based on how TERRA production can be changed, these exciting results open a new door for the development of treatment options for ALT cancers.

Source: 10.1073/pnas.2208669119

Image Credit: Getty

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