New study reveals an unexpected survival mechanism of a subset of cancer cells
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 led by Claus M. Azzalin at Instituto de Medicina Molecular João Lobo Antunes (iMM; Portugal: https:/
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.
*Bruno Silva, Richard Pentz, Ana Margarida Figueira, Rajika Arora, Yong Woo Lee, Charlotte Hodson, Harry Wischnewski, Andrew J. Deans, and Claus M. Azzalin (2019) FANCM limits ALT activity by restricting telomeric replication stress induced by deregulated BLM and R-loops. Nature Communications. Doi: 10.1038/s41467-019-10179-z