MIRIAM CAIMANO

Dottoressa di ricerca

ciclo: XXXIII



Titolo della tesi: Understanding the Molecular Mechanisms Occurring in the Oncogenesis of Brain Tumors: Role of ubiquitylation processes as promising therapeutic target in tumor treatments

Brain tumors are a wide group of intracranial malignancies arising from Central Nervous System (CNS) cells. Tumors deriving from neurons include Medulloblastoma (MB), the most frequent cancerous brain tumor among children that develops in the cerebellum. Instead, Glioblastoma (GB), which starts from glia, represents the most common of malignant primary brain tumors in adults and occurs in supratentorial region of the brain. The molecular heterogeneity that characterizes both tumors, as well as their rapid progression and the occurrence of drug-resistance, limit the effectiveness of the improved therapeutic management making these malignancies difficult to treat. In this scenario, the identification of key molecular players involved in MB and GB tumorigenesis is essential to understand the onset of these devasting tumors thus developing personalized therapy. Targeting components of Ubiquitin Proteasome System (UPS), whose aberrant function are at the roots of several neuropathology establishment, could provide a promising approach to the study of novel and more efficient therapeutic strategies. Exploring novel molecular mechanisms involved in GB tumorigenesis, we identified the RNA-binding E3-ubiquitin ligase MEX3A as a new molecular player in GB. MEX3A belongs to MEX3 family of proteins (MEX3A-D), known to be involved in embryogenesis and differentiation processes, with implications regarding stem cell regulation and carcinogenesis. We found that MEX3A is strongly up-regulated in GB specimens and correlates with low protein levels of RIG-I, a tumor suppressor involved in differentiation, apoptosis and innate immune response. We demonstrated that MEX3A interacts with RIG-I and impairs its protein stability promoting its ubiquitylation and proteasome-dependent degradation. Interestingly, the genetic depletion of MEX3A leads to an increase of RIG-I protein levels and results in the inhibition of GB cell growth both in vitro and in vivo. Our findings unveil a novel molecular mechanism involved in GB tumorigenesis and suggest that targeting MEX3A and RIG-I could open innovative perspectives for new therapeutic approaches in the treatment of GB. Regarding the MB, we focused our study on the Hedgehog (Hh)-dependent MB subgroup (SHH-MB), characterized by an aberrant activation of Hh signaling, a pathway essential in embryonic development and tissue homeostasis. We identified the endoplasmic reticulum aminopeptidase 1 (ERAP1), a key regulator of innate and adaptative anti-tumor immune response, as a positive regulator of Hh pathway. We demonstrated that ERAP1 interacts with the deubiquitinase USP47, displaces the USP47-associated βTrCP, the substrate-receptor subunit of the SCFβTrCP ubiquitin ligase, and promotes βTrCP degradation. This event leads to the modulation of Gli transcription factors, the final effectors of the Hh pathway, and the enhancement of Hh activity. In particular, we found that the inhibition of ERAP1 promotes the degradation of the transcription factor Gli1, and, at the same time, the conversion of the transcription factor Gli3 into the repressor form (Gli3R). Of note, we observed that both genetic and pharmacological inhibition of ERAP1 strongly reduces the growth of Hh-dependent medulloblastoma both in vitro and in vivo. In conclusion, this thesis has been focused on the characterization of molecular mechanisms in the tumorigenic process of some of the most aggressive primary brain tumors such as Glioblastoma and Medulloblastoma. These findings will contribute to understand the tumor biology with significant improvements in cancers diagnosis, management and therapeutic approaches.

Produzione scientifica

11573/1613665 - 2021 - Drug delivery systems for hedgehog inhibitors in the treatment of SHH-medulloblastoma
Caimano, M.; Lospinoso Severini, L.; Loricchio, E.; Infante, P.; Di Marcotullio, L. - 01g Articolo di rassegna (Review)
rivista: FRONTIERS IN CHEMISTRY (Lausanne : Frontiers Media S.A., 2013-) pp. - - issn: 2296-2646 - wos: WOS:000663813400001 (13) - scopus: 2-s2.0-85108348605 (13)

11573/1613699 - 2021 - A new smoothened antagonist bearing the purine scaffold shows antitumour activity in vitro and in vivo
Zarate, A. M.; Espinosa-Bustos, C.; Guerrero, S.; Fierro, A.; Oyarzun-Ampuero, F.; Quest, A. F. G.; Di Marcotullio, L.; Loricchio, E.; Caimano, M.; Calcaterra, A.; Gonzalez-Quiroz, M.; Aguirre, A.; Melendez, J.; Salas, C. O. - 01a Articolo in rivista
rivista: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES (Basel (Matthaeustrasse 11) : Molecular Diversity Preservation International MDPI) pp. - - issn: 1661-6596 - wos: WOS:000690546100001 (11) - scopus: 2-s2.0-85111760377 (11)

11573/1384478 - 2020 - The rna-binding ubiquitin ligase mex3a affects glioblastoma tumorigenesis by inducing ubiquitylation and degradation of rig-i
Bufalieri, F.; Caimano, M.; Severini, L. L.; Basili, I.; Paglia, F.; Sampirisi, L.; Loricchio, E.; Petroni, M.; Canettieri, G.; Santoro, A.; D'angelo, L.; Infante, P.; Di Marcotullio, L. - 01a Articolo in rivista
rivista: CANCERS (Basel: MDPI) pp. 321- - issn: 2072-6694 - wos: WOS:000522477300067 (42) - scopus: 2-s2.0-85079068523 (40)

11573/1560331 - 2020 - Dubs activating the hedgehog signaling pathway: a promising therapeutic target in cancer
Bufalieri, F.; Lospinoso Severini, L.; Caimano, M.; Infante, P.; Di Marcotullio, L. - 01g Articolo di rassegna (Review)
rivista: CANCERS (Basel: MDPI) pp. - - issn: 2072-6694 - wos: WOS:000549233900001 (11) - scopus: 2-s2.0-85086322190 (17)

11573/1559760 - 2020 - Synergistic inhibition of the Hedgehog pathway by newly designed Smo and Gli antagonists bearing the isoflavone scaffold
Romeo, Isabella; Lospinoso Severini, Ludovica; Quaglio, Deborah; Basili, Irene; Ghirga, Francesca; Bufalieri, Francesca; Caimano, Miriam; Balducci, Silvia; Moretti, Marta; Loricchio, Elena; Maroder, Marella; Botta, Bruno; Mori, Mattia; Infante, Paola; Di Marcotullio, Lucia - 04f Poster
congresso: STRATAGEM COST CA17104: New diagnostic and therapeutic tools against multidrug resistant tumors (virtual meeting - online mode)
libro: Synergistic inhibition of the Hedgehog pathway by newly designed Smo and Gli antagonists bearing the isoflavone scaffold - ()

11573/1210601 - 2019 - Mitogen-activated kinase kinase kinase 1 inhibits hedgehog signaling and medulloblastoma growth through GLI1 phosphorylation
Antonucci, Laura; Di Magno, Laura; D'amico, Davide; Manni, Simona; Serrao, Silvia Maria; Di Pastena, Fiorella; Bordone, Rosa; Yurtsever, Zuleyha Nihan; Caimano, Miriam; Petroni, Marialaura; Giorgi, Alessandra; Schininà, Maria Eugenia; Yates Iii, John R; Di Marcotullio, Lucia; De Smaele, Enrico; Checquolo, Saula; Capalbo, Carlo; Agostinelli, Enzo; Maroder, Marella; Coni, Sonia; Canettieri, Gianluca - 01a Articolo in rivista
rivista: INTERNATIONAL JOURNAL OF ONCOLOGY (National Hellenic Research Foundation:48 Vas Constatinou Avenue, Athens 11635 Greece:011 30 1 7241505, Fax: 011 30 1 7241505Editore attuale:PROFESSOR D A SPANDIDOS, 1, S MERKOURI ST, EDITORIAL OFFICE,, ATHENS, GREECE, 116 35. Editore precedente:Editorial Academy of the International Journal of Oncology.) pp. 505-514 - issn: 1019-6439 - wos: WOS:000454923900009 (25) - scopus: 2-s2.0-85058877986 (27)

11573/1304369 - 2019 - 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, Angelo; Pazzaglia, S.; Giannini, G.; Melino, G.; Locatelli, F.; Gulino, A.; Ayrault, O.; Fruci, D.; Di Marcotullio, L. - 01a Articolo in rivista
rivista: NATURE COMMUNICATIONS (London: Nature Publishing Group-Springer Nature) pp. 1-15 - issn: 2041-1723 - wos: WOS:000476877400003 (40) - scopus: 2-s2.0-85069646549 (41)

11573/1321077 - 2019 - A Smo/Gli multitarget hedgehog pathway inhibitor impairs tumor growth
Lospinoso Severini, Ludovica; Quaglio, Deborah; Basili, Irene; Ghirga, Francesca; Bufalieri, Francesca; Caimano, Miriam; Balducci, Silvia; Moretti, Marta; Romeo, Isabella; Loricchio, Elena; Maroder, Marella; Botta, Bruno; Mori, Mattia; Infante, Paola; Di Marcotullio, Lucia - 01a Articolo in rivista
rivista: CANCERS (Basel: MDPI) pp. 1518-1534 - issn: 2072-6694 - wos: WOS:000498826000115 (39) - scopus: 2-s2.0-85073503434 (40)

11573/1559753 - 2019 - Synergistic inhibition of the Hedgehog pathway by newly designed Smo and Gli antagonists bearing the isoflavone scaffold
Romeo, Isabella; Berardozzi, Simone; Bernardi, Flavia; Infante, Paola; Ingallina, Cinzia; Toscano, Sara; De Paolis, Elisa; Alfonsi, Romina; Caimano, Miriam; Botta, Bruno; Mori, Mattia; Di Marcotullio, Lucia; Ghirga, Francesca - 04f Poster
congresso: XII EWDD - 12th European Workshop in Drug Design (Certosa di Pontignano, Siena (Italy))
libro: Synergistic inhibition of the Hedgehog pathway by newly designed Smo and Gli antagonists bearing the isoflavone scaffold - ()

11573/1131161 - 2018 - Synergistic inhibition of the Hedgehog pathway by newly designed Smo and Gli antagonists bearing the isoflavone scaffold
Berardozzi, Simone; Bernardi, Flavia; Infante, Paola; Ingallina, Cinzia; Toscano, Sara; De Paolis, Elisa; Alfonsi, Romina; Caimano, Miriam; Botta, Bruno; Mori, Mattia; Di Marcotullio, Lucia; Ghirga, Francesca - 01a Articolo in rivista
rivista: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY (Editions Scientifique & Medical Elsevier:23 Rue Linois, F 75724 Paris Cedex 15 France:011 33 1 71724646, INTERNET: http://www.elsevier.fr, Fax: 011 33 1 71724664) pp. 554-562 - issn: 0223-5234 - wos: WOS:000443663200039 (33) - scopus: 2-s2.0-85049903501 (32)

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