Dottoressa di ricerca

ciclo: XXXV

supervisore: Prof.ssa Elisabetta Ferretti

Titolo della tesi: MicroRNAs as diagnostic biomarkers and identification of molecular escape mechanism to tyrosine kinase inhibitors (TKI) in Medullary Thyroid Carcinoma

Medullary thyroid cancer (MTC) is a rare neuroendocrine tumor arising from thyroid C cells, with frequent mutations in the rearranged during transfection (RET) or RAS genes. MTC can be hereditary in 20-25% or sporadic in 75-80% of cases. MTC diagnosis is performed by thyroid nodule biopsy with immunohistochemical positivity for calcitonin (Ctn) and Ctn deregulated serum levels, but sporadic MTC is usually diagnosed as an advanced tumour because it arises as solitary thyroid nodule without symptoms. The determination of tumour biomarkers is of primary importance to personalized medicine, mostly for rare tumours as MTC, whose diagnosis is still challenging due to the lack of non-invasive diagnostic biomarkers. Treatment for localized MTC consists of total thyroidectomy but MTC patients that present metastatic or progressive disease receive treatment with tyrosine kinase inhibitors (TKI) that include Cabozantinib and the recent FDA approved selective RET inhibitor, Pralsetinib (Blu-667). A limitation to the efficacy of TKI therapy is the possibility to develop escape mechanisms. As an example, hypoxia may promote the selection of resistant clones. Activation of hypoxia-inducible pathways as resistant mechanism in MTC tumours has been observed after administration of Cabozantinib, however no studies analysed this event after Blu-667 administration. To address these medical needs, I analysed microRNAs (miRNAs) expression in primary samples derived from MTC patients, both plasma and tissue, with the aim to discover non-invasive MTC diagnostic biomarkers. Moreover, I investigated mechanisms involved in the biological activity of Pralsetinib in a MTC cell line (TT cells), specifically in the context of a hypoxic microenvironment. These experiments allowed the identification and validation of a signature of two circulating microRNAs, miR-26b-5p and miR-451a, in two independent cohorts reporting a significant diagnostic performance for MTC. In the second part of my thesis, I investigate the molecular mechanism underlying response and resistance to the selective RET inhibitor Pralsetinib. Indeed, after in vitro administration of selective RET inhibitor, I have demonstrated the existence of a subpopulation of cells that escape Pralsetinib activity, in a RET-independent manner, specifically through the nuclear translocation and subsequent stabilization of the Gli1 protein, the principal transcriptional activator of the Hedgehog (HH)-pathway. In conclusion, I was able to identify circulating microRNAs as potential diagnostic tool and a possible mechanism of TKI treatment resistance in MTC cell line.

Produzione scientifica

11573/1696314 - 2024 - The endocrine disruptor cadmium modulates the androgen-estrogen receptors ratio and induces inflammatory cytokines in luminal (A) cell models of breast cancer
Bimonte, Viviana M; Catanzaro, Giuseppina; Po, Agnese; Trocchianesi, Sofia; Besharat, Zein Mersini; Spinello, Zaira; Curreli, Mariaignazia; Fabi, Alessandra; Bei, Roberto; Milella, Michele; Vacca, Alessandra; Ferretti, Elisabetta; Migliaccio, Silvia - 01a Articolo in rivista
rivista: ENDOCRINE (New York, Berlin: Springer Totowa, N.J. : Humana Press) pp. - - issn: 1559-0100 - wos: WOS:001120921200002 (0) - scopus: 2-s2.0-85176741955 (0)

11573/1681989 - 2024 - Prospective validation study of a novel integrated pathway based on clinical features, MRI biomarkers and microRNAs for early detection of prostate cancer
Pecoraro, Martina; Catanzaro, Giuseppina; Conte, Federica; Besharat, Zein Mersini; Messina, Emanuele; Laschena, Ludovica; Trocchianesi, Sofia; Splendiani, Elena; Sciarra, Alessandro; Catalano, Carlo; Paci, Paola; Ferretti, Elisabetta; Panebianco, Valeria - 01a Articolo in rivista
rivista: EUROPEAN UROLOGY ONCOLOGY ([Amsterdam]: European Association of Urology; Published by Elsevier B.V.) pp. - - issn: 2588-9311 - wos: WOS:001171264200001 (1) - scopus: 2-s2.0-85181477687 (1)

11573/1682746 - 2023 - Circulating miR-26b-5p and miR-451a as diagnostic biomarkers in medullary thyroid carcinoma patients
Besharat, Z M; Trocchianesi, S; Verrienti, A; Ciampi, R; Cantara, S; Romei, C; Sabato, C; Noviello, T M R; Po, A; Citarella, A; Caruso, F P; Panariello, I; Gianno, F; Carpino, G; Gaudio, E; Chiacchiarini, M; Masuelli, L; Sponziello, M; Pecce, V; Ramone, T; Maino, F; Dotta, F; Ceccarelli, M; Pezzullo, L; Durante, C; Castagna, M G; Elisei, R; Ferretti, E - 01a Articolo in rivista
rivista: JOURNAL OF ENDOCRINOLOGICAL INVESTIGATION (Sprimger Milano: Kurtis) pp. 2583-2599 - issn: 1720-8386 - wos: WOS:001002889000001 (2) - scopus: 2-s2.0-85161261291 (1)

11573/1691730 - 2023 - Network analysis identifies circulating miR-155 as predictive biomarker of type 2 diabetes mellitus development in obese patients: a pilot study
Catanzaro, Giuseppina; Conte, Federica; Trocchianesi, Sofia; Splendiani, Elena; Bimonte, Viviana Maria; Mocini, Edoardo; Filardi, Tiziana; Po, Agnese; Besharat, Zein Mersini; Gentile, Maria Cristina; Paci, Paola; Morano, Susanna; Migliaccio, Silvia; Ferretti, Elisabetta - 01a Articolo in rivista
rivista: SCIENTIFIC REPORTS (London: Springer Nature London: Nature Publishing Group) pp. - - issn: 2045-2322 - wos: WOS:001106459000065 (3) - scopus: 2-s2.0-85176149771 (5)

11573/1691552 - 2023 - Circulating cell-free DNA (cfDNA) in patients with medullary thyroid carcinoma is characterized by specific fragmentation and methylation changes with diagnostic value
Citarella, Anna; Besharat, Zein Mersini; Trocchianesi, Sofia; Autilio, Tanja Milena; Verrienti, Antonella; Catanzaro, Giuseppina; Splendiani, Elena; Spinello, Zaira; Cantara, Silvia; Zavattari, Patrizia; Loi, Eleonora; Romei, Cristina; Ciampi, Raffaele; Pezzullo, Luciano; Castagna, Maria Grazia; Angeloni, Antonio; Elisei, Rosella; Durante, Cosimo; Po, Agnese; Ferretti, Elisabetta - 01f Lettera, Nota
rivista: BIOMARKER RESEARCH (London : BioMed Central) pp. - - issn: 2050-7771 - wos: WOS:001071556900001 (0) - scopus: 2-s2.0-85171850558 (0)

11573/1677425 - 2023 - Hedgehog-GLI and Notch Pathways Sustain Chemoresistance and Invasiveness in Colorectal Cancer and Their Inhibition Restores Chemotherapy Efficacy
Citarella, Anna; Catanzaro, Giuseppina; Besharat, Zein Mersini; Trocchianesi, Sofia; Barbagallo, Federica; Gosti, Giorgio; Leonetti, Marco; Di Fiore, Annamaria; Coppola, Lucia; Autilio, Tanja Milena; Spinello, Zaira; Vacca, Alessandra; De Smaele, Enrico; Venneri, Mary Anna; Ferretti, Elisabetta; Masuelli, Laura; Po, Agnese - 01a Articolo in rivista
rivista: CANCERS (Basel: MDPI) pp. 1471- - issn: 2072-6694 - wos: WOS:000947305400001 (7) - scopus: 2-s2.0-85149860378 (8)

11573/1682747 - 2023 - Molecular mechanisms of the tyrosine kinase inhibitor pralsetinib activity in in-vitro models of medullary thyroid carcinoma: Aberrant activation of the HH-Gli signaling pathway in acquired resistance
Trocchianesi, Sofia; Po, Agnese; Citarella, Anna; Spinello, Zaira; Rughetti, Aurelia; Besharat, Zein Mersini; Autilio, Tanja Milena; Pecce, Valeria; Verrienti, Antonella; Elisei, Rossella; Durante, Cosimo; Catanzaro, Giuseppina; Ferretti, Elisabetta - 01a Articolo in rivista
rivista: BIOMÉDECINE & PHARMACOTHÉRAPIE (Paris: Editions Scientifique & Medical Elsevier) pp. 114995- - issn: 0753-3322 - wos: WOS:001020719000001 (1) - scopus: 2-s2.0-85161303043 (1)

11573/1633475 - 2022 - Identification and validation of mir-222-3p and mir-409-3p as plasma biomarkers in gestational diabetes mellitus sharing validated target genes involved in metabolic homeostasis
Filardi, Tiziana; Catanzaro, Giuseppina; Emanuela Grieco, Giuseppina; Splendiani, Elena; Trocchianesi, Sofia; Santangelo, Carmela; Brunelli, Roberto; Guarino, Elisa; Sebastiani, Guido; Dotta, Francesco; Morano, Susanna; Ferretti, Elisabetta - 01a Articolo in rivista
rivista: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES (Basel (Matthaeustrasse 11) : Molecular Diversity Preservation International MDPI) pp. 1-16 - issn: 1661-6596 - wos: WOS:000786176700001 (16) - scopus: 2-s2.0-85128127175 (19)

11573/1644501 - 2022 - Cell-Target-Specific Anti-Inflammatory Effect of Empagliflozin: In Vitro Evidence in Human Cardiomyocytes
Giannattasio, Silvia; Citarella, Anna; Trocchianesi, Sofia; Filardi, Tiziana; Morano, Susanna; Lenzi, Andrea; Ferretti, Elisabetta; Crescioli, Clara - 01a Articolo in rivista
rivista: FRONTIERS IN MOLECULAR BIOSCIENCES (Lausanne : Frontiers Media S.A., 2014-) pp. - - issn: 2296-889X - wos: WOS:000810898900001 (5) - scopus: 2-s2.0-85132285347 (6)

11573/1449521 - 2021 - Role of tissue and circulating microRNA and DNA as biomarkers in medullary thyroid cancer
Chiacchiarini, Martina; Trocchianesi, Sofia; Besharat, Zein Mersini; Po, Agnese; Ferretti, Elisabetta - 01a Articolo in rivista
rivista: PHARMACOLOGY & THERAPEUTICS (Elsevier Science Limited:Oxford Fulfillment Center, PO Box 800, Kidlington Oxford OX5 1DX United Kingdom:011 44 1865 843000, 011 44 1865 843699, EMAIL:,, INTERNET:,, Fax: 011 44 1865 843010) pp. 107708- - issn: 0163-7258 - wos: WOS:000619674700001 (7) - scopus: 2-s2.0-85095586540 (9)

11573/1683419 - 2021 - Hedgehog driven regulatory network sustains chemoresistance and mesenchymal phenotype in Colorectal Cancer cells
Citarella, A.; Catanzaro, G.; Besharat, Z. M.; Barbagallo, F.; Trocchianesi, S.; Sabato, C.; Autilio, T. M.; Asquino, A.; Vacca, A.; Venneri, M. A.; Ferretti, E.; Po, A. - 04f Poster
libro: - ()

11573/1444376 - 2020 - Hedgehog-GLI signalling promotes chemoresistance through the regulation of ABC transporters in colorectal cancer cells
Po, A.; Citarella, A.; Catanzaro, G.; Besharat, Z. M.; Trocchianesi, S.; Gianno, F.; Sabato, C.; Moretti, M.; De Smaele, E.; Vacca, A.; Fiori, M. E.; Ferretti, E. - 01a Articolo in rivista
rivista: SCIENTIFIC REPORTS (London: Springer Nature London: Nature Publishing Group) pp. - - issn: 2045-2322 - wos: WOS:000567440100012 (25) - scopus: 2-s2.0-85089600783 (29)

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