Breakthrough Discovery in Understanding the Processes of Metastasis and Ageing

Scientists of the Institute of Molecular and Translational Medicine (IMTM) at the Faculty of Medicine, Palacký University, have participated in the discovery of a new mechanism through which the cell “perceives” mechanical vibrations. Together with their colleagues from the Czech Republic and abroad, they have made an important step towards understanding the processes of tumour metastasis, stem cell migration, and ageing. The study was published in July by one of the most prestigious biomedical journals in the world, Cell.

The main protagonist in the discovery is the ATR protein, a protein kinase involved in sensing DNA damage, subsequently launching a complicated cascade of biochemical reactions leading to DNA repair and cell cycle arrest. The proper functioning of the cascade is vital for maintaining genome stability and prevention of mutations leading to tumour transformation. This well-known role of ATR has now been complemented with the new finding. Scientists have observed that whenever the cells have to cope with mechanical stress, whether as a result of intracellular processes or external forces, ATR responds to mechanical vibrations, becomes activated, and relocates to the nuclear envelope.

ATR enzyme helps cells to cope with crises

“Just as anchoring ropes hold a ship in place, chromatin, the complex of DNA and proteins making up the contents of the nucleus of a cell, attaches to the nuclear membrane. During mechanical stress, ATR kinase promotes detachment of chromatin from this anchoring,” said Peter Vanek from the IMTM. The ATR enzyme thus prevents damaging of the subtle nuclear structures, at the same time launching cellular responses typical for DNA damage. This is how it enables the cell to cope with the critical situation.

During cellular migration, which is common for instance in early embryonic development, in stem cell regeneration of ageing or damaged tissue, or in metastatic formation of tumour cells, the degree of mechanical stress is extraordinary. ATR probably represents the key modulator of these processes, enabling cells to cope with mechanical stress.

“From this point of view, the biochemical cascade of proteins activated by ATR, including the kinase itself, may be a potential tool in diagnostics and treatment of metastatic tumours or certain degenerative diseases related to ageing,” added Vanek.

Result of multidisciplinary collaboration

The new findings about the cellular enzyme ATR, a genome protector that has been investigated for its ability to reduce the formation and growth of tumours, were made possible by the interconnection of several disciplinary approaches at various institutes. Apart from the IMTM and the Institute of Molecular Genetics of the Academy of Sciences of the Czech Republic in Prague, the research was conducted by research institutions in Milan (Fondazione Istituto di Oncologia Molecolare), Singapore (National University of Singapore) and Denmark (Danish Cancer Society Research Centre). The discovery resulted from multidisciplinary collaboration with the use of techniques and knowledge from advanced microscopy, molecular biology, mechanical engineering, and electrophysiology. The laboratories involved are led by Professor Marco Foiani from Milan and Professor Jiří Bártek, who also works for the IMTM.

This scientific work represents one of the breakthrough insights into the problem. Deformability or plasticity is one of the most important, but as yet barely explored characteristics of cells. It enables the cells to survive various forms of mechanical stress. Simultaneously, it is a necessary prerequisite for cell migration, when the cells are forced to pass through very narrow openings in body tissues. At present, the molecular mechanisms accompanying the mechanical deformation of cells are to a large extent still unclear.

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