Study of genetic condition leads to discovery of mechanism that promotes the formation of renal cysts and tumours, thanks to the support of Telethon and AIRC

At the Telethon Institute of Genetics and Medicine (Tigem) in Pozzuoli, the team led by Andrea Ballabio has described in Nature* how the study of a rare genetic condition has provided the key to understanding a mechanism that leads to the formation of cysts and tumours in certain organs, in particular the kidneys. Supported by Fondazione Telethon, Fondazione AIRC for cancer research and Regione Campania, the study included the participation the European Institute of Oncology (IEO) and the Institute of Cell Biology at the University of Innsbruck.

Andrea Ballabio, Tigem

The first signatories of the article are Gennaro Napolitano and Chiara Di Malta, two researchers who came back to Italy following considerable work experience in California and Texas, respectively, to work at Tigem with Ballabio to study TFEB, a gene that orchestrates cellular response to external stimuli. Ballabio brought this gene into the spotlight for the first time in 2009 in Science. "Transcription factor EB (TFEB) is a protein that coordinates the expression and hence the activity of many other genes", explains Napolitano. "In response to environmental stimuli, such as the absence of nutrients, TFEB is activated and switches on specific genes that can respond to the stimulus, or conversely, it is inhibited and its target genes remain switched off. For several years we have been working on understanding the cellular activities regulated by this gene, ranging from the disposal of cellular waste to the control of cell metabolism. In recent years we have been focusing on mTOR, a protein that blocks the action of TFEB when nutrients are available i.e. when the cell can obtain energy from outside. Conversely, TFEB is activated when there is a lack of nutrients and internal reserves must be used."

Another protein, folliculin, also contributes to blocking TFEB, and this is faulty in the rare genetic syndrome Birt-Hogg-Dubé (BHD), which was named after the three Canadian doctors who discovered it in 1977. This syndrome has been reported in over 100 families throughout the world, and the common characteristic among these patients is the tendency to form renal and pulmonary cysts, and skin lesions. The renal cysts often deteriorate to form fully-fledged malignant tumours. "We therefore wondered whether or not TFEB had a role in the clinical manifestation of the disease, and consequently if intervening on its activity could have a therapeutic effect", explains Di Malta. "The experiments carried out with laboratory animals confirmed our theory - when the folliculin gene was deactivated we observed the formation of numerous cysts in renal cells, precisely as with patients suffering from BHD due to their genetic defect. When we subsequently also deactivated TFEB in the laboratory animals, we observed a complete recovery with the total disappearance of the cysts."

In other words, a physiological mechanism of adaptation to the availability of nutrients for normal cells may become a hazardous advantage when the cells reproduce excessively and require a lot of energy. Blocking the activity of TFEB could be a winning strategy in the case of different tumours - whether it concerns the kidney, pancreas or skin, such as melanoma - in addition to genetic conditions characterised by the tendency of some tissues to proliferate excessively, such as in the case of polycystic kidney disease or tuberous sclerosis.

"This study was the product of a fruitful long term collaboration between our group and those of Dr. Paolo Di Fiore at the European Institute of Oncology in Milan and Dr. Lukas Huber at the Institute of Cell Biology at the University of Innsbruck The first step will be to test whether the mechanism that we discovered also operates in other genetic conditions and tumours", concludes Ballabio. Concurrently, we will be searching for molecules that selectively inhibit the activity of TFEB, thanks to the expertise acquired by our institute over the years in the large-scale screening of potential drugs directed at a specific target, which we are also currently making available for the Covid-19 emergency. This study demonstrates yet again how studying rare genetic conditions has wide-reaching spin-offs. Rarity is closely linked to the fact that they depend on fundamental biological mechanisms, and this makes them unique models for studying the mechanisms of life. Studying them is therefore important not only for the benefit of those who are affected directly, but potentially also for people affected by other diseases."

*Gennaro Napolitano, Chiara Di Malta, Alessandra Esposito, Mariana E.G. de Araujo, Salvatore Pece, Giovanni Bertalot, Maria Matarese, Valerio Benedetti, Angela Zampelli, Taras Stasyk, Diletta Siciliano, Alessandro Venuta, Marcella Cesana, Claudia Vilardo, Edoardo Nusco, Jlenia Monfregola, Pier Paolo Di Fiore, Lukas A. Huber, Andrea Ballabio. “A substrate-specific mTORC1 pathway underlies Birt-Hogg-Dube’ syndrome”.

Il tuo browser non è più supportato da Microsoft, esegui l'upgrade a Microsoft Edge per visualizzare il sito.