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New study reveals unexpected mechanism of survival of a subset of cancer cells

By Cristina Bastos On 28 May, 2019 2019 | iMM Corner Comments Off on New study reveals unexpected mechanism of survival of a subset of cancer cells No tags

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

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Index – News # 90 | may. 2019
 The Faculty exists because of the students
 2018 Activity Report
 Professor Fausto J. Pinto becomes member of ANM Brazil
 Ana Rita Mendonça Bello wins the 2019 Professor Francisco Pulido Valente Teaching Award
 Carmo Fonseca recebe Prémio como símbolo de Portugalidade
 Carolina whose eyes speak for themselves
 A 6 people conversation…with the Students of the Pedagogical Board
 Um desafio chamado AEFML – Andreia Daniel
 A class with Professor Susana Constantino
 Miguel Castanho, the Professor
 The professor who breaks the ice with the students – Prof. Maria José Diógenes
 The first day visiting the Faculty of Medicine
 Article by Professor Miguel Castanho in the Visão magazine
 Professor Maria do Carmo Fonseca among the most influential women
 Professor Catarina Sousa Guerreiro “around food”
 Professor Joana Sousa talks about Obesity
 For A Healthy Heart – Healthy Children
 There are official projects designed for Student Integration.
 CEMBE: our contribution to value-based healthcare.
 Publicações Científicas (FMUL / HSM / IMM) abril – maio | 2019
 Bial Award in Biomedicine 2019
 The survival of (some) tumour cells and the hideouts of the parasites
 New study reveals unexpected mechanism of survival of a subset of cancer cells
 Where do parasites hide?
 Cooperation Protocol between the FMUL and Nutrium
 Agreement between the Faculty of Medicine of the University of Lisbon and the Champalimaud Foundation strengthen ties of collaboration in Portugal
 Professor Miguel Castanho interviewed by Saúde Mais Tv
 Passadiços do Paiva: O 34º aniversário da CPFMUL em Arouca
 The Teaching of Medicine (part I)
 Remembering Amato Lusitano
 Coro e Orquestra Médicos de Lisboa voltam a dar-nos música!
 Solvin’it – Sinfonia dos Sentidos
 Já abriu a 7ª Edição dos Prémios SANTA CASA Neurociências
 Conversa a três
 A despedida a Fernando Lopes da Silva
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100 AnosPropriedade e Edição: Faculdade de Medicina da Universidade de Lisboa NIPC: 502662875  Periodicidade: Mensal  Diretor: Prof. Doutor Fausto J. Pinto Conselho Editorial: Prof. Doutor Fausto J. Pinto, Profª. Doutora Ana Sebastião, Prof. Doutor Mamede de Carvalho, Prof. Doutor António Vaz Carneiro, Prof. Doutor Miguel Castanho, Dr. Luís Pereira  Equipa Editorial:  Ana Raquel Moreira, Cristina Bastos, Isabel Varela, Joana Sousa, Maria de Lurdes Barata, Rui Gomes, Sónia Teixeira  Colaboração:  Gabinete de Relações Públicas, Internacionais e Comunicação  Versão Inglesa: AP|PORTUGAL- Language Services  Conceção: Metatexto, Lda. e-mail: news@medicina.ulisboa.pt  Sede do Editor e Sede da Redação: Avenida Prof. Egas Moniz, 1649-028 Lisboa Estatuto Editorial Anotado na ERC 

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