VITTORIO CASTALDO

Dottore di ricerca

ciclo: XXXV


supervisore: Rita Mancini-Luigi Fattore/ Angela Catizone
relatore: Rita mancini

Titolo della tesi: Dissecting the role of novel oncomiRs and their molecular targets in the evolution of resistance to target therapies in melanoma

AIMS: They have been: a) To characterize the migratory and invasive properties of drug-resistant melanoma cells and to assess the correlation with miR-4443 and miR-4488 overexpression; b) To investigate whether the enforced overexpression of miR-4443 or miR-4488 in drug sensitive melanoma cells is able to phenocopy the biological properties of drug-resistant cells; c) To identify miR-4443 and miR-4488 potential targets and unveil the molecular pathways affected in melanoma. RESULTS: I demonstrated that BRAF-mutant melanoma cells rendered drug resistant to BRAFi have enhanced migrative/invasive properties as compared to their drug sensitive counterparts. Moreover, drug-sensitive melanoma cells transiently transfected with miR-4443/miR-4488 mimics are able to phenocopy the migratory/invasive behaviour of drug-resistant cells. Furthermore, Confocal microscopy analyses showed that MAPKi-resistant A375 cells are increased in size, number of stress fibers and filopodia. In silico predictions of miR-4443/miR-4488 target genes combined to literature studies allowed to hypothesize the intermediated filament protein Nestin, as a promising candidate. Coherently with this, experimental data showed that Nestin is strongly down-regulated in drug-resistant cells in which miR-4443/miR-4488 are in contrast up-regulated. Finally, luciferase assays as well as WB and FACS analyses confirmed the predictions. CONCLUSIONS: I demonstrated that a) drug-resistant cells enhanced migratory and invasive properties as compared to sensitive counterparts, b) this phenotype is influenced by miR-4443/miR-4488, which are upregulated in drug resistant cells and c) I identified a novel oncomiRs-Nestin axis as responsible for the regulation of migrative/invasive properties of metastatic melanoma. Altogether, these evidences unveiled novel non-genetic mechanisms centered around the deregulation of two novel oncomiRs as responsible for the evolution of drug resistance to targeted therapies in BRAF-mutant melanomas; these findings may potential therapeutic implications.

Produzione scientifica

11573/1661031 - 2023 - Oncosuppressive miRNAs loaded in lipid nanoparticles potentiate targeted therapies in BRAF-mutant melanoma by inhibiting core escape pathways of resistance
Fattore, Luigi; Cafaro, Giordana; Di Martile, Marta; Campani, Virginia; Sacconi, Andrea; Liguoro, Domenico; Marra, Emanuele; Bruschini, Sara; Stoppoloni, Daniela; Cirombella, Roberto; De Nicola, Francesca; Pallocca, Matteo; Ruggiero, Ciro F; Castaldo, Vittorio; Catizone, Angiolina; Del Bufalo, Donatella; Viglietto, Giuseppe; Vecchione, Andrea; Blandino, Giovanni; Aurisicchio, Luigi; Fanciulli, Maurizio; Ascierto, Paolo A; De Rosa, Giuseppe; Mancini, Rita; Ciliberto, Gennaro - 01a Articolo in rivista
rivista: ONCOGENE (Macmillan Magazines Limited:Porters South Crinian Street, London N1 9XW United Kingdom:011 44 207 8334000, 011 44 171 8434982, Fax: 011 44 207 812358) pp. 293-307 - issn: 0950-9232 - wos: WOS:000886818700001 (7) - scopus: 2-s2.0-85142445757 (13)

11573/1670654 - 2022 - Identification of a miRNA-based non-invasive predictive biomarker of response to target therapy in BRAF-mutant melanoma
Ruggiero, Ciro Francesco; Fattore, Luigi; Terrenato, Irene; Sperati, Francesca; Salvati, Valentina; Madonna, Gabriele; Capone, Mariaelena; Valenti, Fabio; Di Martino, Simona; Mandoj, Chiara; Liguoro, Domenico; Castaldo, Vittorio; Cafaro, Giordana; Simeone, Ester; Vanella, Vito; Russillo, Michelangelo; Conti, Laura; Cuda, Giovanni; Giannarelli, Diana; Antonio Ascierto, Paolo; Mancini, Rita; Ciliberto, Gennaro - 01a Articolo in rivista
rivista: THERANOSTICS (Wyoming, N.S.W. : Ivyspring International Publisher, 2011-) pp. 7420-7430 - issn: 1838-7640 - wos: WOS:000877833900002 (13) - scopus: 2-s2.0-85141245744 (12)

11573/1541409 - 2021 - The promise of liquid biopsy to predict response to immunotherapy in metastatic melanoma
Fattore, L.; Ruggiero, C. F.; Liguoro, D.; Castaldo, V.; Catizone, A.; Ciliberto, G.; Mancini, R. - 01g Articolo di rassegna (Review)
rivista: FRONTIERS IN ONCOLOGY (Lausanne : Frontiers Editorial Office, 2011-) pp. 1-12 - issn: 2234-943X - wos: WOS:000635554000001 (17) - scopus: 2-s2.0-85103599813 (18)

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