The Hedgehog Signalling Pathway is fundamental for the correct development of organisms, but it can  be extremely damaging if stimulated inappropriately. In fact, the aberrant activation of the pathway is responsible for the formation of wide range of tumours, including medulloblastomas, the most common cerebral tumour in children.

This is why it is crucial to comprehend the mechanisms that regulate the Hedgehog Signalling Pathway and study its involvement in the process that lead to the tumorigenesis to develop new increasingly less toxic custom-tailored therapeutic strategies.

A research team coordinated by Prof. Lucia Di Marcotullio from the Sapienza Department of Molecular Medicine, in collaboration with Doriana Fruci  at the Onco-haematology Department at the  Rome “Bambino Gesù” Paediatric Hospital, studied the role of ERAP1 (a protein involved in immune response) in tumoral development, identifying this molecule as an important regulator of the Hedgehog Signalling Pathway and a promising therapeutic target in tumours. The results of the study have been published on Nature Communications.

The researchers working on this project, funded by the Italian Association for Cancer Research (AIRC), demonstrated that, through various experimental models (both in vitro and in vivo), if ERAP1 is inactivated, it triggers a chain of events that block the growth of the tumour.

In a previous study, the team had demonstrated that the inactivation of the ERAP1 gene kicks off a powerful rejection mechanism by the immune system through T Cell Lymphocytes and Natural Killer Cells, two types of immune cells dedicated to anti-tumoral activities.

“In this study,” points out Prof. Di Marcotullio, “we have gained new understanding of the function of ERAP1 in the development of tumours, demonstrating that its inhibition blocks the growth of tumours on a range of fronts, acting directly on cellular proliferation and indirectly making tumoral cells more susceptible to elimination by immune cells.”

This new discovery could have a great potential and open up important new therapeutic scenarios. Moreover, it is also probably that the use of drugs capable of inhibiting ERAP1 may be useful for the treatment of other paediatric and adult tumours.

References:

ERAP1 promotes Hedgehog-dependent tumorigenesis by controlling USP47-mediated degradation of βTrCP - Bufalieri F., Infante P., Bernardi F., Caimano M., Romania P., Moretti M., Lospinoso Severini L., Talbot J., Melaiu O., Tanori M., Di Magno L., Bellavia D., Capalbo C., Puget S., De Smaele E., Canettieri G., Guardavaccaro D., Busino L., Peschiaroli A., Pazzaglia S., Giannini G., Melino G., Locatelli F., Gulino A., Ayrault O., Fruci D., Di Marcotullio L. - Nature Communications, 10, Article number: 3304 (2019) DOI: 10.1038/s41467-019-11093-0

Further Information

Lucia Di Marcotullio 

Department of Molecular Medicine, Sapienza University of Rome

lucia.dimarcotullio@uniroma1.it