Embedded at the end of chromosomes are structures called "telomeres" that in normal cells become shorter as cells divide. As the shortening progresses it triggers cell proliferation arrest or death. Cancer cells adopt different strategies to overcome this control mechanism that keeps track of the number of times that a cell has divided.

One of these strategies is the alternative lengthening of telomeres (ALT) pathway, which guarantees unlimited proliferation capability. Now, a research group has discovered that a human enzyme named FANCM (Fanconi anemia, complementation group M) is absolutely required for the survival of ALT tumor cells. The results were now published in the journal Nature Communications.

ALT tumors are approximately 10% of the human tumors, and often develop in children (for example, juvenile osteosarcoma) and they are particularly resistant to conventional chemotherapy. Contrary to the canonical telomere elongation mechanism that activates the enzyme telomerase, these tumor cells specifically use this alternative pathway which is insensitive to therapeutic approaches based on telomerase inhibition", explains the group leader.

"Previous studies have shown that a sustained physiological telomere damage must be maintained in these cells to promote telomere elongation. This scenario implies that telomeric damage levels be maintained within a specific threshold that is high enough to trigger telomere elongation, yet not too high to induce cell death", says the first author of this work.

Using a series of molecular biology-, cell biology- and biochemistry-based experiments, the research team found an essential role for FANCM, a component of the DNA damage repair machineries of the cell. "What we have found is that ALT cells require the activity of the FANCM in order to prevent telomere instability and consequent cell death", says the author. "When we remove FANCM from ALT tumor cells, telomeres become heavily damaged and cells stop dividing and die very quickly. This is not observed in tumor cells that express telomerase activity or in healthy cells, meaning that is a specific feature of ATL tumor cells", explains the senior author.

"In our view, this is very exciting because it indicates that transiently drugging FANCM activity in ALT cells should lead to very fast cell death specifically in these cells, and sets the potential basis for an alternative therapeutic protocol for this type of tumors", adds the senior author.

https://imm.medicina.ulisboa.pt/en/imm-lisboa/news/archive/novo-estudo-revela-um-mecanismo-de-sobrevivencia-inesperado-de-um-subconjunto-de-celulas-tumorais/

https://www.nature.com/articles/s41467-019-10179-z

http://sciencemission.com/site/index.php?page=news&type=view&id=publications%2Ffancm-limits-alt&filter=22