IRENE BASILI

Dottoressa di ricerca

ciclo: XXXV


supervisore: Lucia Di Marcotullio
relatore: Lucia Di Marcotullio
co-supervisore: Lucia Di Marcotullio

Titolo della tesi: Deciphering the role of AMBRA1 in the control of the Hedgehog signaling pathway and in the tumorigenesis of medulloblastoma

Medulloblastoma (MB) is the most common childhood brain tumor that originates from cerebellar development alterations. Multi-omics analysis has defined four MB molecular subgroups - Wingless (WNT), Sonic-Hedgehog (SHH), Group 3 (G3) and Group 4 (G4) - each with distinct molecular signatures and clinical features. Among them, SHH is the most abundant and genetically characterized. Given its crucial role in tumorigenesis, SHH signaling has emerged as druggable target for MB, offering a valuable opportunity to overcome the pitfalls of the current anti-cancer therapies. Unveiling the molecular mechanisms underlying the control of this important developmental pathway could lead to the identification of new drivers and promising therapeutic strategies for cancer treatment. To address this aim, my research project has been focused on the characterization of novel interactors of RENKCTD11 (here REN), a substrate receptor subunit of the Cullin3-RING ubiquitin ligase complex (CRL3REN) and tumor suppressor lost in ~30% of human SHH-MBs. Starting from the mass spectrometry analysis we identified AMBRA1, a well-known pro-autophagic regulators, as potential interactor of CRL3REN. We demonstrate that CRL3REN binds and induces polyubiquitylation and proteasome-mediated degradation of AMBRA1. Interestingly, we demonstrated that AMBRA1 acts as a positive regulator of the SHH pathway enhancing Gli1 protein stability, the final effector of SHH signalling. We found that AMBRA1 interacts with βTrCP, the substrate receptor of SCFβTrCP ubiquitin ligase known to promote proteolysis of Gli1, and impairs βTrCP-associated Gli1. This event results in the accumulation of Gli1, and the enhancement of SHH activity. Remarkably, genetic depletion of AMBRA1 strongly reduces SHH-dependent MB growth both in vitro and in vivo. In conclusion, results obtained by my Ph.D. project identify AMBRA1 as a previously unknown regulator of the SHH pathway and unveil a novel molecular mechanism responsible of SHH-MB tumorigenesis. Our findings highlight AMBRA1 as a promising therapeutic target for the development of more effective intervention for SHH-dependent tumors care.

Produzione scientifica

11573/1692856 - 2024 - SALL4 is a CRL3^REN/KCTD11 substrate that drives Sonic Hedgehog-dependent medulloblastoma
Lospinoso Severini, Ludovica; Loricchio, Elena; Navacci, Shirin; Basili, Irene; Alfonsi, Romina; Bernardi, Flavia; Moretti, Marta; Conenna, Marilisa; Cucinotta, Antonino; Coni, Sonia; Petroni, Marialaura; De Smaele, Enrico; Giannini, Giuseppe; Maroder, Marella; Canettieri, Gianluca; Mastronuzzi, Angela; Guardavaccaro, Daniele; Ayrault, Olivier; Infante, Paola; Bufalieri, Francesca; Di Marcotullio, Lucia - 01a Articolo in rivista
rivista: CELL DEATH AND DIFFERENTIATION (Nature Publishing Group:Brunel Road Houndmills, Basingstoke RG21 6XS United Kingdom:011 44 20 78334000, EMAIL: institutions@natureny.com, INTERNET: http://www.nature.com, Fax: 011 44 20 78434640) pp. - - issn: 1350-9047 - wos: WOS:001119029000002 (3) - scopus: 2-s2.0-85178929821 (2)

11573/1560455 - 2021 - Design and synthesis of new withaferin A inspired hedgehog pathway inhibitors
Bonandi, E.; Mori, M.; Infante, P.; Basili, I.; Di Marcotullio, L.; Calcaterra, A.; Catti, F.; Botta, B.; Passarella, D. - 01a Articolo in rivista
rivista: CHEMISTRY-A EUROPEAN JOURNAL (Wiley-VCH Verlag GmBH:PO Box 101161, D 69451 Weinheim Germany:011 49 6201 606147, EMAIL: service@wiley-vch.de, INTERNET: http://www.wiley-vch.de, Fax: 011 49 6201 606328) pp. 8350-8357 - issn: 0947-6539 - wos: WOS:000646619600001 (5) - scopus: 2-s2.0-85105325845 (6)

11573/1560767 - 2021 - Harnessing the activation of RIG-I like receptors to inhibit glioblastoma tumorigenesis
Bufalieri, Francesca; Basili, Irene; Di Marcotullio, Lucia; Infante, Paola - 01g Articolo di rassegna (Review)
rivista: FRONTIERS IN MOLECULAR NEUROSCIENCE (Lausanne: Frontiers Research Foundation, 2008-) pp. - - issn: 1662-5099 - wos: WOS:000675519000001 (6) - scopus: 2-s2.0-85111069951 (6)

11573/1472828 - 2021 - Glabrescione B delivery by self-assembling micelles efficiently inhibits tumor growth in preclinical models of Hedgehog-dependent medulloblastoma
Infante, P.; Malfanti, A.; Quaglio, D.; Balducci, S.; De Martin, S.; Bufalieri, F.; Mastrotto, F.; Basili, I.; Garofalo, M.; Lospinoso Severini, L.; Mori, M.; Manni, I.; Moretti, M.; Nicoletti, C.; Piaggio, G.; Caliceti, P.; Botta, B.; Ghirga, F.; Salmaso, S.; Di Marcotullio, L. - 01a Articolo in rivista
rivista: CANCER LETTERS (Elsevier Science Ireland Limited:PO Box 85, Limerick Ireland:011 353 61 709600, 011 353 61 61944, EMAIL: usinfo-f@elsevier.com, INTERNET: http://www.elsevier.com, Fax: 011 353 61 709114) pp. 220-231 - issn: 0304-3835 - wos: WOS:000604424500023 (21) - scopus: 2-s2.0-85097086576 (25)

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 (41) - scopus: 2-s2.0-85079068523 (40)

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 - ()

11573/1559014 - 2020 - mPEG5kDa-cholane/Glabrescione B delivery system as promising tool for the treatment of Hh-dependent tumors
Vergine, Valeria; Infante, Paola; Malfanti, Alessio; Quaglio, Deborah; Balducci, Silvia; De Martin, Sara; Bufalieri, Francesca; Mastrotto, Francesca; Basili, Irene; Garofalo, Mariangela; Lospinoso Severini, Ludovica; Mori, Mattia; Manni, Isabella; Moretti, Marta; Nicoletti, Carmine; Piaggio, Giulia; Caliceti, Paolo; Botta, Bruno; Ghirga, Francesca; Salmaso, Stefano; Di Marcotullio, Lucia - 04f Poster
congresso: Stratagem cost WG2 on Synthesis and nanodelivery strategies for new therapeutic tools against Multidrug Resistant Tumours (online)
libro: Cost Action 17104(Stratagem) - ()

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 (38) - scopus: 2-s2.0-85073503434 (39)

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