Dottoressa di ricerca

ciclo: XXXIV

Titolo della tesi: Hedgehog driven regulatory network sustains chemoresistance through ABC transporters and mesenchymal phenotype in Colorectal Cancer cells

Colorectal cancer (CRC) is a leading cause of mortality and morbidity. Despite the advances in therapeutic strategies, chemoresistance continues to be a major issue. CRC chemoresistance mechanisms are heterogeneous and not fully elucidated, thus understanding mechanisms related to aggressive features remains a pivotal goal for the development of efficient therapies. In this context, there is evidence that CRC with deregulated Hedgehog-GLI1 (HH-GLI1) pathway as well as Notch signalling pathway are associated with poor prognosis. HH-GLI1 pathway is a developmental pathway involved in the control of proliferation, differentiation and stem cell maintenance. Its aberrant activation is linked to CRC tumorigenesis, tumour maintenance and cancer stem cell phenotype. The NOTCH1 pathway is another developmental pathway involved in CRC aggressiveness, which is associated with epithelial-mesenchymal transition (EMT). In addition, the crosstalk between HH-GLI1 and NOTCH1 signalling is fundamental in the development of the normal colonic mucosa. The aim of my PhD thesis was to investigate molecular mechanisms through which HH-GLI1 pathway regulates CRC resistance to chemotherapy. In the first part of my thesis, I demonstrated that HH-GLI1 regulates chemoresistance in CRC cellular models by up-regulating the ATP-binding cassette (ABC) transporters. Using chromatin immunoprecipitation experiments, I observed that GLI1 transcriptionally regulates six ABC transporters binding their promoter region. Then, I showed that chemoresistant cells express high levels of GLI1 and ABC transporters. Finally, I described that GLI1 inhibition disrupts the transporters up-regulation and restores chemo-sensitivity. In the second part of my thesis, I investigated other aspects of chemoresistance evaluating the NOTCH1 pathway along with HH-GLI1 after chemotherapy stress in CRC cells. I used two models of chemoresistance, each representative of common driver mutations in CRC: BRAFV600E and KRASG13D. In BRAFV600E mutated CRC, the resistance to apoptosis induced by chemotherapy is mainly sustained by HH-GLI, while in KRASG13D driven CRC the resistance is driven by the concurrent activation of HH-GLI and NOTCH pathways, and the inhibition of both is crucial to revert the resistant phenotype. Moreover, I set up CRC organoid models and I used them to evaluate also epithelial–mesenchymal transition (EMT) aspects in CRC. In conclusion, the data obtained from my studies led me to describe new molecular mechanisms that regulate CRC resistance to chemotherapy.

Produzione scientifica

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)

11573/1691552 - 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)

11573/1649691 - 2022 - MiR-1248: a new prognostic biomarker able to identify supratentorial hemispheric pediatric low-grade gliomas patients associated with progression
Catanzaro, Giuseppina; Besharat, Zein Mersini; Carai, Andrea; Jäger, Natalie; Splendiani, Elena; Colin, Carole; Po, Agnese; Chiacchiarini, Martina; Citarella, Anna; Gianno, Francesca; Cacchione, Antonella; Miele, Evelina; Diomedi Camassei, Francesca; Gessi, Marco; Massimi, Luca; Locatelli, Franco; Jones, David T W; Figarella-Branger, Dominique; Pfister, Stefan M; Mastronuzzi, Angela; Giangaspero, Felice; Ferretti, Elisabetta - 01a Articolo in rivista
rivista: BIOMARKER RESEARCH (London : BioMed Central) pp. - - issn: 2050-7771 - wos: WOS:000812504600001 (2) - scopus: 2-s2.0-85132122098 (2)

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)

11573/1683419 - 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: - ()

11573/1605136 - 2021 - Significance of sex differences in ncrnas expression and function in pregnancy and related complications
Vari, R.; Scazzocchio, B.; Filardi, T.; Citarella, A.; Bellenghi, M.; Masella, R.; Santangelo, C. - 01g Articolo di rassegna (Review)
rivista: BIOMEDICINES (Basel : MDPI) pp. 1-16 - issn: 2227-9059 - wos: WOS:000727548000001 (3) - scopus: 2-s2.0-85118281768 (3)

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)

11573/1292099 - 2018 - The PHD finger protein Spp1 has distinct functions in the Set1 and the meiotic DSB formation complexes
Adam, C.; Guerois, R.; Citarella, Anna; Verardi, L.; Adolphe, F.; Beneut, C.; Sommermeyer, V.; Ramus, C.; Govin, J.; Coute, Y.; Borde, V. - 01a Articolo in rivista
rivista: PLOS GENETICS (San Francisco, CA : Public Library of Science, c2005-) pp. e1007223- - issn: 1553-7404 - wos: WOS:000426361900028 (32) - scopus: 2-s2.0-85043332238 (30)

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