Dottore di ricerca

ciclo: XXXIV

supervisore: Prof.ssa Rita Mancini

Titolo della tesi: miR-579-3p restrains tumor heterogeneity to overcome resistance to target therapies in metastatic melanoma

My PhD thesis has been directed to the study of the mechanisms responsible for the development of drug resistance in melanoma. A large subset of melanoma patients harbors activating mutations in the BRAF oncogene at position V600. These mutations sensitize tumors to inhibition by inhibitors of BRAF in combination with inhibitors of the downstream kinase MEK. This has led in the past years to approval of combo therapies composed of a BRAF and a MEK inhibitor for these patients. These combo therapies give rise to strong objective responses and provide significant improvements in overall survival. However their duration in time is strongly limited by the development of drug resistance. While initial studies focused mainly in genetic mechanisms at the basis of de novo drug resistance, in recent years several groups, including my PhD supervisor, focused their attention of non genetic mechanisms and in particular to phenotypic changes underlying drug adaptation. In this context several microRNAs have been shown to play an important role, in particular miR-579-3p which was discovered some years ago as an oncosuppressor and antagonist of drug resistance in the lab of my supervisor. In order to assess the role of this microRNA my PhD thesis has been directed initially to build and characterize a human melanoma cell line engineered to express miR-579-3p in a transcriptionally inducible manner. After the initial characterization the cell line has been subjected to a series of studies which have led to the demonstration that miR-579 is able to severely affect the development of drug resistance. A particular emphasis has been given to bulk RNA sequencing studies as well as to single cell mass cytometry which have shown that induction of expression of miR-579-3p is able to impair drug adaptive mechanism and to strongly diminish the degree of the heterogeneity in a isogenic cell population of melanoma cells when these cells are exposed to the selective pressure of BRAF and MEK inhibitors.

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 (3) - scopus: 2-s2.0-85142445757 (3)

11573/1686679 - 2023 - ERK signaling pathway is constitutively active in NT2D1 non-seminoma cells and its inhibition impairs basal and HGF-activated cell proliferation
Gesualdi, Luisa; Berardini, Marika; Maria Scicchitano, Bianca; Castaldo, Clotilde; Bizzarri, Mariano; Filippini, Antonio; Riccioli, Anna; Schiraldi, Chiara; Ferranti, Francesca; Liguoro, Domenico; Mancini, Rita; Ricci, Giulia; Catizone, Angela - 01a Articolo in rivista
rivista: BIOMEDICINES (Basel : MDPI) pp. 1-24 - issn: 2227-9059 - wos: WOS:001038004500001 (0) - scopus: 2-s2.0-85174479276 (1)

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 (6) - scopus: 2-s2.0-85141245744 (5)

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 (16) - scopus: 2-s2.0-85103599813 (15)

11573/1574470 - 2021 - miR-125a-5p impairs the metastatic potential in breast cancer via IP6K1 targeting
Minini, M.; Senni, A.; He, X.; Proietti, S.; Liguoro, D.; Catizone, A.; Giuliani, A.; Mancini, R.; Fuso, A.; Cucina, A.; Cao, Y.; Bizzarri, M. - 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:, INTERNET:, Fax: 011 353 61 709114) pp. 48-56 - issn: 0304-3835 - wos: WOS:000696948200001 (7) - scopus: 2-s2.0-85109143153 (10)

11573/1379250 - 2020 - In vitro biophysical and biological characterization of lipid nanoparticles Co-encapsulating oncosuppressors miR-199b-5p and miR-204-5p as potentiators of target therapy in metastatic melanoma
Fattore, L.; Campani, V.; Ruggiero, C. F.; Salvati, V.; Liguoro, D.; Scotti, L.; Botti, G.; Ascierto, P. A.; Mancini, Rita; De Rosa, G.; Ciliberto, G. - 01a Articolo in rivista
rivista: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES (Basel (Matthaeustrasse 11) : Molecular Diversity Preservation International MDPI) pp. - - issn: 1661-6596 - wos: WOS:000529890200026 (15) - scopus: 2-s2.0-85081533314 (14)

11573/1441572 - 2020 - Drug tolerance to target therapy in melanoma revealed at single cell level. What next?
Liguoro, Domenico; Fattore, Luigi; Mancini, Rita; Ciliberto, Gennaro - 01a Articolo in rivista
rivista: BIOCHIMICA ET BIOPHYSICA ACTA-REVIEWS ON CANCER (Elsevier Scientific Publ. Co.) pp. 1-9 - issn: 0304-419X - wos: WOS:000592916400036 (4) - scopus: 2-s2.0-85091902305 (4)

11573/1328068 - 2019 - Single cell analysis to dissect molecular heterogeneity and disease evolution in metastatic melanoma
Fattore, Luigi; Ruggiero, Ciro Francesco; Liguoro, Domenico; Mancini, Rita; Ciliberto, Gennaro - 01a Articolo in rivista
rivista: CELL DEATH & DISEASE (Nature Group) pp. 827- - issn: 2041-4889 - wos: WOS:000497970200004 (33) - scopus: 2-s2.0-85074253202 (33)

11573/1315761 - 2019 - ErbB3 Phosphorylation as Central Event in Adaptive Resistance to Targeted Therapy in Metastatic Melanoma. Early Detection in CTCs during Therapy and Insights into Regulation by Autocrine Neuregulin
Ruggiero, Ciro Francesco; Malpicci, Debora; Fattore, Luigi; Madonna, Gabriele; Vanella, Vito; Mallardo, Domenico; Liguoro, Domenico; Salvati, Valentina; Capone, Mariaelena; Bedogni, Barbara; Ascierto, Paolo Antonio; Mancini, Rita; Ciliberto, Gennaro - 01a Articolo in rivista
rivista: CANCERS (Basel: MDPI) pp. 1-16 - issn: 2072-6694 - wos: WOS:000498826000022 (19) - scopus: 2-s2.0-85073435278 (21)

11573/1174288 - 2018 - Reprogramming miRNAs global expression orchestrates development of drug resistance in BRAF mutated melanoma
Fattore, L; Ruggiero, Cf; Pisanu, Me; Liguoro, Domenico; Cerri, A; Costantini, S; Capone, F; Acunzo, M; Romano, G; Nigita, G; Mallardo, D; Ragone, C; Carriero, Mv; Budillon, A; Botti, G; Ascierto, Pa; Mancini, R; Ciliberto, G. - 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:, INTERNET:, Fax: 011 44 20 78434640) pp. 1-16 - issn: 1350-9047 - wos: WOS:000470970300007 (46) - scopus: 2-s2.0-85053853797 (46)

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