MARILISA CONENNA

Dottoressa di ricerca

ciclo: XXXVI


supervisore: Marella Maroder
co-supervisore: Francesca Bartolini

Titolo della tesi: Role of the cytoskeleton regulator inverted formin 2 (INF2) in SHH-medulloblastoma tumorigenesis

Medulloblastoma (MB) is the most common childhood brain tumor, arising from alterations in cerebellar development. Through multi-omics analysis, four distinct molecular subgroups of MB have been defined: 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 prevalent subgroup, characterized by genetic alterations in critical regulators of Hedgehog (HH) signaling, an evolutionally conserved developmental pathway. The aberrant activation of HH signaling is involved in the onset of a wide range of malignancies, thus emerging in the last years as a promising druggable target. To date, the therapeutic strategy to inhibit HH signaling at the level of the Smoothened (SMO) receptor, a positive regulator and key transducer of the pathway, has been a failure. This is due to drug-resistance and the existence of non-canonical SMO-independent mechanisms of activation of Gli transcriptional factors, the final effectors of the HH pathway. For these reasons, characterizing the complex mechanisms underlying HH signaling regulation is urgently needed to design novel therapeutic approaches. In the last years, growing body of evidence has underlined as defects in the cytoskeletal remodeling determines several hallmarks of tumor cells: aberrant cell division, genomic instability, migration, and invasion. In particular, functional and genetic alterations affecting formins, a family of key proteins for the regulation of cytoskeletal dynamics, have been associated with a broad spectrum of tumors. Recent studies have also revealed the existence of a connection between formins and the non-canonical activation of the HH pathway, suggesting their involvement in the onset of HH-driven tumors. In this area of studies, my Ph.D. research activity focused to define the role of formins, and in particular of the inverted formin 2 (INF2), in the regulation of the HH pathway and in the tumorigenesis of HH-MB. Our results identified INF2 as a negative regulator of HH signaling, with an opposite effect to the mDIA2 formin. We found that the overexpression of INF2 counteracts the positive effects of mDIA2 on Gli1, the final and most powerful effector of HH signaling, by reducing both its transcriptional activity and HH-dependent expression. Accordingly, the INF2 genetic silencing increases mRNA and protein levels of Gli1 as well as the proliferation of granule cell progenitors (GCPs), the cells of origin of MB. Moreover, a correlation between increased INF2 protein expression and time dependent switching off of HH signaling was observed during normal cerebellum development in mice, showing an opposite trend to mDIA2. Interestingly, INF2 protein levels were strongly reduced in murine HH-MB samples, contrary to what observed for mDIA2. Notably, the overexpression of INF2 in HH-MB primary cells significantly inhibits the cell proliferation as consequence of the reduction of Gli1 expression levels, and increases the stiffness of primary MB cells, a feature that has been recently correlated to the invasiveness of tumor cells. Overall, these findings strongly support a negative role of INF2 in the regulation of HH signaling, and highlight this protein as an emerging therapeutic target for the design of innovative options for the treatment of HH-MB. We expect our studies will pave the way to study cytoskeleton remodeling proteins as a novel area of investigation in tumor biology of HH-MB.

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)

11573/1687539 - 2023 - Exploring the potential of anthraquinone-based hybrids for  identifying a novel generation of antagonists for the Smoothened receptor in HH-dependent tumour
Quaglio, Deborah; Infante, Paola; Cammarone, Silvia; Lamelza, Lara; Conenna, Marilisa; Ghirga, Francesca; Adabbo, Gennaro; Pisano, Luca; Di Marcotullio, Lucia; Botta, Bruno; Mori, Mattia - 01a Articolo in rivista
rivista: CHEMISTRY (Weinheim: Wiley-VCH-Verl..) pp. - - issn: 1521-3765 - wos: WOS:001071179800001 (1) - scopus: 2-s2.0-85172686997 (0)

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