The research team (from left to right): Margarida Figueira; Claus Azzalin; Bruno Silva

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, group leader at the iMM has discovered that a human enzyme named FANCM (Fanconi anaemia, complementation group M) is absolutely required for the survival of ALT tumour cells. The results were now published in the open access journal Nature Communications* and suggest that future strategies targeting the activity of this molecule in ALT tumour cells can constitute the basis of a novel therapeutic protocol for the treatment of these tumours.

ALT tumours are approximately 10% of the human tumours, 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 tumour cells specifically use this alternative pathway which is insensitive to therapeutic approaches based on telomerase inhibition”, explains Claus Azzalin.

“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, post-doctoral researcher and 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 the 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 tumour cells, telomeres become heavily damaged and cells stop dividing and die very quickly. This is not observed in tumour cells that express telomerase activity or in healthy cells, meaning that it is a specific feature of ATL tumour cells”, explains Claus Azzalin .

“In our view, this is very exciting because it indicates that transiently interfering in 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 tumours”, adds Claus Azzalin .

This study was developed at the iMM in collaboration with the Genome Stability Unit and the Department of Medicine at St. Vincent’s Institute of Medical Research and the University of Melbourne (Australia) and the Institute of Biochemistry at ETH Zürich (Switzerland). This study was supported by the Swiss National Science Foundation, the European Molecular Biology Organization (EMBO), Fundação para a Ciência 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

Chromosomes of ALT tumour cells without FANCM activity. Telomeric DNA is shown in green, at the end of the chromosomes shown in red. The arrows point to dissociated telomeric DNA in chromosomes, indicating a severe telomere abnormality.

Inês Domingues

Director of Communication of iMM João Lobo Antunes