Red Light at the Pediatric Brain Tumor
Medulloblastoma is the most common brain tumor in childhood. Current therapies combine surgery, radiotherapy, and chemotherapy, which despite a good chance of recovery, cause severe side effects, such as permanent cognitive impairments. For this reason, the discovery of alternative and innovative treatments is priority.
A recent study by Lucia Di Marcotullio of the Department of Molecular Medicine of Sapienza University of Rome, in collaboration with Paola Infante of CLNS @ Sapienza (Italian Institute of Technology, IIT), has found a new molecular mechanism, whose alteration is responsible for development of medulloblastoma. The results of the work, which represents a nodal point for the development of new therapeutic strategies, are published in the international journal Nature Communications.
Medulloblastoma is caused by molecular alterations that determine aberrant activity of key proteins belonging to a signal trasduction pathway that controls the growth and migration of neuronal cells.
"This signaling, called Hedgehog (Hh) pathway - Di Marcotullio explains - is emerging as an attractive druggable pathway because its uncontrolled activation is implicated in several cancers, thus representing an important target for more effective and therefore less toxic anticancer therapies".
Researchers from Sapienza University and CLNS @ Sapienza (IIT) have found that, a modification of a known tumor suppressor, the SuFu protein, favors the association with another key molecule of the signaling pathway, the Gli3 protein. This process induces Gli3 to act as a red light for tumor growth, enhancing its ability to suppress cell proliferation.
To confirm these results, mutations of SuFu protein prevented the association between the two molecules, inducing Gli3 to act as a green light, thereby favoring cell proliferation and contributing to the pathogenesis of medulloblastoma.
This discovery adds an important piece to the understanding of the complex regulation of the Hh pathway and explains how mutations in its key components can contribute to the emergence of a highly aggressive tumor such as medulloblastoma.
"This work - Di Marcotullio concludes - encourages us to pursue with enthusiasm the study of the molecular bases of medulloblastoma. Indeed, an intensive basic research is an essential tool to unveil the complex and still obscure biology of tumors and to develop novel and more effective therapeutic approaches for the treatment of this malignant brain tumor”.
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
Lucia Di Marcotullio - Department of Molecular Medicine
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