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New THERAPIES for Treating Medulloblastomas

16-04-2018

Medulloblastomas are the most widespread type of tumour amongst children. Current therapy associates surgery with radio- and chemotherapy, which has a good success rate, but it may cause serious collateral damage, including permanent cognitive issues. Thus, research on alternative innovative cures are fundamental.

A recent study, conducted by Professor Lucia Di Marcotullio from the Sapienza Department of Molecular Medicine in collaboration with Paola Infante from the Italian Institute of Technology, has led to the discovery of a new molecular mechanism that when altered is responsible for the development of medulloblastoma. The results of the study, which represent a crucial milestone for the development of new therapeutic strategies, were published on Nature Communications.

Medulloblastoma is caused by molecular alterations that lead to the anomalous behaviour of the signal proteins involved in the development and migration of nervous cells. “This signalling pathway, known as the Hedgehog Pathway, is the object of great interest in oncology because it can be responsible for the onset of a wide range of tumours. Therefore, it is an important target for efficient cancer therapies with a lesser toxicity.” 

The Sapienza and IIT researchers discovered that the alteration of a well-known tumour suppressor, the SuFu Protein, promotes its association with another key molecule of the signalling pathway, Protein Gli3. This process allows the Gli3 Protein to block the development of the tumour by reinforcing the molecule’s ability to limit cellular growth.

The results were cross-checked by observing what happens when the SuFu Protein is altered. Following the modification of the protein’s molecular mechanisms – and thus the impediment for the two molecules to associate – the researchers observed that Protein Gli3 allowed cellular proliferation, contributing to the pathogenesis of medulloblastomas.

This discovery sheds new light on the understanding of the complex regulation of the Hedgehog Pathway and reveals how mutations of its key components can contribute to very aggressive tumours, such as medulloblastomas.

“The results that we have achieved,” explains Professor Di Marcotullio, “encourage us to continue studying the molecular basis of medulloblastoma through intensive basic research, an indispensable tool to reveal the complex and obscure biology of tumours and develop new custom-tailored therapeutic approaches for the treatment of these tumours.”

Reference:

Itch/β-arrestin2-dependent non-proteolytic ubiquitylation of SuFu controls Hedgehog signalling and medulloblastoma tumorigenesis - Paola Infante, Roberta Faedda, Flavia Bernardi, Francesca Bufalieri, Ludovica Lospinoso Severini, Romina Alfonsi, Daniela Mazzà, Mariangela Siler, Sonia Coni, Agnese Po, Marialaura Petroni, Elisabetta Ferretti, Mattia Mori, Enrico De Smaele, Gianluca Canettieri, Carlo Capalbo, Marella Maroder, Isabella Screpanti, Marcel Kool, Stefan M. Pfister, Daniele Guardavaccaro, Alberto Gulino & Lucia Di Marcotullio - Nature Communications volume 9, Article number: 976 (2018) doi:10.1038/s41467-018-03339-0