An interdisciplinary research conducted by a group of researchers from IFOM and University of Milan reported an unprecedented role for ATR: a protein, already known for its DNA repair and tumor suppressor function. Researchers demonstrated that ATR is also the key component of the tumor cell plasticity and, therefore, of its metastatic spread. This completely unexpected role has important implications for the understanding of metastases and for the identification of targeted therapeutic solutions. This interdisciplinary study, which was recently published in the prestigious scientific journal “Nature Communications”, took place in the laboratories of IFOM in combining advanced microscopy and mechano-biology techniques.

IFOM in Milan reported major advancement in our understanding of metastases, the main cause of cancer mortality, paving the way for novel therapeutic approaches.

By combining multidisciplinary experimental approaches with advanced microscopy and mechano-biology, the group of Prof. Marco Foiani in IFOM (Italy) has discovered an unexpected role of ATR, in maintaining cell integritiy during metastasis. Baptized six years ago by the same team as “Diapason protein", ATR has long been known for its role as a sensor of DNA damage and as mediator of repair processes by activating P53, the 'guardian of the genome' that prevents mutations, thereby counteracting the onset of tumors. In 2014 the "Genome Integrity" laboratory of Professor Foiani, reported that ATR plays a role of mechanical sensor in healthy cells, warning and protecting cells against the mechanical vibrations originating within the nucleus or from the outside by external mechanical stress (Cell 2014). Extending this observation, the laboratory emerged with this new study, published in Nature Communications, showing that the ATR mediated modulation of cellular plasticity is crucial factor for tumor metastases.

"During metastasis, cancer cell disseminates from the primary site, invades the body and colonizes on the remotest tissues. In this process, metastatic cells experience enormous mechanical stress”- explains Foiani - “To counteract this stress, tumor cells must implement metamorphic strategies: that is, deform, crush and compress everything, including the nucleus, in order to pass through the narrowest pores of the host tissue”. Strategies involve rendering the cell nucleus more elastic, more resistant to the obstacles presented by interstitial migration, which is precisely regulated by ATR.

In the absence of ATR, the nuclear envelope of the cancer cell tends to be more rigid, and therefore more fragile, with a tendency to lose nuclear DNA and inevitably explode, resulting in unsuccessful metastatic dissemination.
The evidence emerging from the data now published in Nature Communications, finally explains why the ATR inhibitors which currently are being tested in various stages of clinical trials are empirically effective. "Conceptually - comments Foiani - it is paradoxical that the same gene is a tumor suppressor and at the same time also a promoter of metastases for exactly the same ability it has to influence the shape and rigidity of the cell nucleus, but this shows that cancer is a pathology driven by both mechanical as well as genetic parameters, as mechanical forces can interfere with the stability of the genome ".

To demonstrate the novel role of ATR in cellular mechanics, the IFOM team of researchers took a completely different experimental approach instead of traditional methods used to study DNA damage molecules such as ATR. "Through multiple international collaborations with mechano-biology and biophysics field-experts combined with IFOM core facilities, we designed the most advanced biophysical and mechano-biological assays utilising microscopy, electron microscopy, proteomics and microfabtication” explains Gururaj Rao Kidyoor, lead-author of the study “In order to observe the mechanical properties of the cells we used atomic force microscopy, microfabricated silicone CHIPs and in-house built microfludic devices. Microfluidic compression device developed by IFOM mechano-medicine unit headed by Qingsen Li, helped us to quantitatively analyse cellular response to a measured amount of mechanical stress.” In order to validate the results in an animal model, several in-vivo experiments were also performed including cancer metastasis assay and neuronal migration assay in developing mouse brain.

The study conducted in the IFOM laboratories, which lasted six years and was possible thanks to the support of the AIRC Foundation, not only broadens the understanding of the reasons for the success of ATR inhibitors, but also opens up the possibility of developing a new family of drugs that act only on the mechanical response pathway of ATR, potentially allowing to greatly reduce the effects of ATR inhibitors on healthy cells and tissues and, therefore, not compromising its essential DNA repair role.

INFORMAZIONI EDITORIALI

• JOURNAL: Nature Communications
• TITLE: ATR is essential for preservation of cell mechanics and nuclear integrity during interstitial migration