Unexpected survival mechanism of a subset of cancer cells revealed

Now, a research group led by Claus M. Azzalin at Instituto de Medicina Molecular João Lobo Antunes (iMM) 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 open access journal Nature Communications. Future strategies targeting the activity of this molecule in ALT tumor cells can constitute the basis of a novel therapeutic protocol for the treatment of these tumors.

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 Claus M. Azzalin, group leader at iMM.

"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 Bruno Silva, 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 Bruno Silva. "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 Claus M. Azzalin.

"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 Claus Azzalin.

This study was developed at iMM in collaboration with the Genome Stability Unit and the Department of Medicine at St. Vincent's Institute of Medical Research and University of Melbourne (Australia) and the Institute of Biochemistry at ETH Zu?rich (Switzerland).

This study was supported by the Swiss National Science Foundation, the European Molecular Biology Organization, the Fundac?a?o para a Cie?ncia e a Tecnologia, the Cancer Council of Victoria, Australian National Health and Medical Research Council, the Buxton Trust and the Victorian Government's OIS Program.