ATR is an enzyme that helps maintain the integrity of the genome. When it does not work properly it can lead to conditions such as cancer, neurological disorders and heart disease. But new research shows that ATR also affects the elasticity of cells.
‘These dual functions of ATR, on the genome and on cell elasticity, have very important differences,’ says Marco Foiani, scientific director of IFOM, a cancer research institute in Milan, Italy. ‘While the first is protective towards preventing tumours, the second might be negative – we suspect that ATR might be needed for the metastasis of cancer cells.’
With support from the EU-funded MECHANOCHECK project, Foiani hired postdoctoral researcher Qingsen Li from Singapore to use his mechanical engineering skills to determine how ATR affects cell elasticity.
Li used an atomic-force microscope to measure the stiffness of cells and their nuclei. ‘ATR defective cells were found to be twice as soft as normal cells,’ Li says. ‘This finding allowed us to demonstrate that ATR influences interstitial migration and metastasis.’
In a pioneering series of experiments, Li designed two devices: one to stretch cells and the other to compress them. He confirmed that cells lacking in ATR were softer and less resilient than normal cells and thus less likely to survive being squeezed or stretched.
‘To further validate the discovery, we used microfabricated channels to mimic a blood capillary and investigated how cells migrate through those constrictions,’ Li explains. He found that cells without ATR were fatally damaged. ‘They literally explode,’ says Foiani. ‘And that’s because of a lack of stiffness. It is amazing to watch this.’
Foiani speculates that this may explain why drugs known to inhibit the function of ATR can be effective in chemotherapy. The softer, weaker cancer cells are less able to push through other tissues to form secondary tumours.
He also thinks the findings may be relevant to Seckel syndrome, a rare and fatal disease where the nervous system does not grow properly, possibly due to a lack of ATR which weakens the developing nerve cells.
The team are now using Li’s devices to study the role of ATR in heart muscle, where the cells are continually stretching and relaxing, in the hope of better understanding some forms of heart disease.
The project ended in March 2018 and Li now leads his own mechanomedicine technology group at IFOM. ‘IFOM provided the ideal training environment to pursue my proposed project and reinforce my creative capacity in the production and implementation of innovative technologies,’ he says.
He is working with TTFactor, a technology transfer company set up by IFOM and two other Italian institutions to commercialise innovations in cancer research. The cell-stretching device has already been patented and a patent for the cell-compression device has been filed.
Li’s work was supported by a Marie Skłodowska-Curie Individual Fellowship, a scheme Foiani describes as ‘fantastic’. ‘To be able to attract a mechanical engineer to work on biomedical problems is so important for us,’ he says. ‘Qingsen not only changed my lab, he changed the entire institute!
‘In IFOM, we now have a programme in collaboration with the Mechanobiology Institute in Singapore. So, we started from biophysics, then we went to mechanobiology and now it’s mechanomedicine which is our direction now.’