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New mechanism that senses the mechanical vibrations of the cells and controls cellular plasticity.

Discovery of a new mechanism that senses the mechanical vibrations of the cells and controls cellular plasticity: A step forward in the understanding of cancer metastasis, stem cells and the ageing-associated diseases

This interdisciplinary research effort, conducted jointly by the Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University Olomouc and Institute of Molecular Genetics, Czech Academy of Sciences in Prague, together with research Institutes in Milano, Singapore and Denmark, has identified the ATR protein, known for its role as DNA defender and tumor suppressor, as the engine of cellular plasticity. This completely unexpected role has important implications for the understanding of metastasis and stem cells, including the serious stem cell-associated diseases of advanced age. The discovery published in Cell (on July 31, 2014), one of the most prestigious global biomedical journals, was made due to international collaboration, by combining advanced microscopy, molecular biology and mechanical engineering and electrophysiology techniques.

Cellular plasticity: cells use it as a defense mechanism and for migration; however, the molecular aspects behind this characteristic are still largely a mystery. Research published today in Cell and conducted at several laboratories, and headed by Prof. Marco Foiani from Milano and Prof. Jiri Bartek at the IMTM/UPOL and IMG/AVCR has just identified the protein that gives cells the gift of plasticity. The protagonist of this discovery is the ATR protein, already known for its crucial role as a damage sensor in DNA repair processes and, therefore in tumor suppression. In fact, the function of the ATR protein is to provide a cellular ‘alarm’ that warns of DNA damage and activates p53, known as "guardian of the genome" because of its role in preserving genomic stability by preventing mutations and therefore cancer.

But research conducted using engineering techniques and published today in Cell reveals a completely new role for ATR: whenever cells undergo mechanical stress, either from inside the nucleus (such as changes in chromosome condensation during cell cycle) or from outside of the cell, ATR senses the mechanical vibrations and immediately becomes activated and moves to the cell nuclear membrane. This newly discovered reaction of the cell provides the cell with plasticity to protect it from the stress. Thus, ATR would have a major role in modulating cellular plasticity, an important capacity both in the response to mechanical stress and during migration, for example during metastasis.

But there is more. The research reveals another unexpected aspect, which could have further implications for cancer research: we know that stem cells have a high level of plasticity that they gradually lose as they differentiate. The scientists behind this discovery published today in Cell propose that ATR and stem cell plasticity are closely linked together. In the future, the goal is to broaden our interdisciplinary research both in the area of tumor metastasis and in cellular differentiation and ageing-associated health issues, to look at the application of possible therapies.