LUISA GESUALDI

Dottoressa di ricerca

ciclo: XXXIV


supervisore: PROF.SSA ANGIOLINA CATIZONE, PROF.SSA GIULIA RICCI

Titolo della tesi: C-Met-activated signalling pathways promote malignant behaviour of NT2D1 non-seminoma cell line

Biological issues – c-MET/HGF axis acts as key regulator of different physiological processes during pre-and post-natal development of many organs and tissues, including the male gonad. However, the deregulation of this system is a well-known feature of malignant phenotype in several cancers and for this reason it has been considered a potential target for therapeutic purpose. Little is known about c-MET/HGF in Testicular Germ Cell Tumours (TGCTs): in the last decade our group studied c-MET/HGF expression and role on three TGCTs derived cell lines (TCam-2, NCCIT, NT2D1) and in histological samples of all major variants of Type II TGCTs. We found NT2D1 non-seminoma cells as the highest expressing cellular line, with respect to the seminoma ones. In accordance with this observation, NT2D1 presented the greatest response to HGF administration. Even in tissue biopsies, non-seminoma lesions showed a higher c-MET membranous staining than seminoma ones; in addition, HGF immunoreactivity is more evident in embryonal carcinoma (non-seminoma) biopsies indicating a link between testicular niche and tumor type. We also studied several adaptors of c-MET-activated pathways, demonstrating firstly a key role of SRC in the HGF-dependent malignant behavior of NT2D1 cells. It is fair to highlight that even PI3K/AKT and the mitogen-activated protein kinases/extracellular signal-regulated kinase (MAPK/ERK) pathways are effective adaptors activated by HGF, and that they appear upregulated in several cancer lesions. Aim – For this reason, in this PhD thesis, we studied the effects induced by HGF treatment on NT2D1 cells, focusing on the role of both PI3K/AKT and MAPK/ERK pathways in the NT2D1 biological responses. Results – To this aim we evaluated phospho- and total AKT and ERK1/2 proteins, both in basal condition and after HGF administration. Moreover, using a pharmacological approach (that is the use of the selective PI3K inhibitor, LY294002, and MEK1/2 inhibitor U0126), we demonstrated that ERK pathway has a role in basal NT2D1 cell proliferation, whereas PI3K/AKT pathway does not. Considering the importance of the micro-environment for tumors growth, and the overexpression of HGF in embryonal carcinoma lesions, we also evaluated the effects of HGF-treatment in NT2D1 cells cultured with or without U0126 or LY294002. We analyzed cell proliferation, collective migration and chemotaxis, as well as morphological modifications. Moreover, we started to study the impact of HGF administration on NT2D1 cell secretome. The administration of LY294002 together with HGF, reverts the HGF-dependent activation of cell proliferation and chemotaxis and blocks the collective migration of NT2D1 cells at levels even below the basal culture condition. Conversely, the administration of U0126 together with HGF, reverts the HGF-dependent activation of cell proliferation, but surprisingly does not exert the same effect on cell collective migration. Intriguingly, the use of U0126 alone significantly promotes the acquisition of an «invading phenotype», and collective migration of NT2D1 cells. Trying to explain this observation we found that the inhibition of ERK activation, mediated by U0126 used alone, resulted in the compensatory activation of the AKT-mediated pathway. This observation, in our opinion, can at least in part explain the results obtained and let us hypothesize that an EMT of NT2D1 cells occurred after U0126 and HGF administration even when used as single drugs. However, the study of EMT markers gave variable results, at the moment, and needs to be further analyzed. Conclusion– All together these observations, indicate that the inhibition of single onco-adaptor protein could exert paradoxical effects. These data highlight how the molecular features of each oncological lesion should be investigated in depth before setting-up the therapy and how microenvironmental cues could modify the response to oncological therapies. This stimulates further investigations of testicular secretome that could allow predicting responders and not-responders to TGCTs personalized target therapies.

Produzione scientifica

11573/1677380 - 2023 - Microgravity Exposure Alterations of Cellular Junctions Proteins in TCam-2 Cells: Localization and Interaction
Berardini, Marika; Gesualdi, Luisa; Ferranti, Francesca; Addolorata Mariggiò, Maria; Morabito, Caterina; Guarnieri, Simone; Ricci, Giulia; Catizone, Angiolina - 01h Abstract in rivista
rivista: BIOLOGY AND LIFE SCIENCES FORUM (Basel: MDPI) pp. - - issn: 2673-9976 - wos: (0) - scopus: (0)

11573/1688712 - 2023 - Simulated microgravity exposure induces antioxidant barrier deregulation and mitochondria enlargement in TCam-2 cell spheroids
Berardini, Marika; Gesualdi, Luisa; Morabito, Caterina; Ferranti, Francesca; Reale, Anna; Zampieri, Michele; Karpach, Katsiaryna; Tinari, Antonella; Bertuccini, Lucia; Guarnieri, Simone; Catizone, Angela; Addolorata Mariggiò, Maria; Ricci, Giulia - 01a Articolo in rivista
rivista: CELLS (Basel: mdpi-Molecular Diversity Preservation International) pp. 1-20 - issn: 2073-4409 - wos: WOS:001057595600001 (1) - scopus: 2-s2.0-85168737077 (0)

11573/1677424 - 2023 - Microgravity Exposure Induces Antioxidant Barrier Deregulation and Mitochondrial Structure Alterations in TCam-2 Cells
Gesualdi, Luisa; Berardini, Marika; Ferranti, Francesca; Reale, Anna; Zampieri, Michele; Karpach, Katsiaryna; Mariggiò, Maria A.; Morabito, Caterina; Guarnieri, Simone; Catizone, Angiolina; Ricci, Giulia - 01h Abstract in rivista
rivista: BIOLOGY AND LIFE SCIENCES FORUM (Basel: MDPI) pp. - - issn: 2673-9976 - wos: (0) - scopus: (0)

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)

11573/1678015 - 2023 - Myo-inositol reverses TGF-β1-induced EMT in MCF-10A non-tumorigenic breast cells
Monti, Noemi; Dinicola, Simona; Querqui, Alessandro; Fabrizi, Gianmarco; Fedeli, Valeria; Gesualdi, Luisa; Catizone, Angiolina; Unfer, Vittorio; Bizzarri, Mariano - 01a Articolo in rivista
rivista: CANCERS (Basel: MDPI) pp. 1-19 - issn: 2072-6694 - wos: WOS:000980913000001 (1) - scopus: 2-s2.0-85153876283 (1)

11573/1677423 - 2023 - Microgravity-Induced Metabolic Response in 2D and 3D TCam-2 Cell Cultures
Morabito, Caterina; Guarnieri, Simone; Berardini, Marika; Gesualdi, Luisa; Ferranti, Francesca; Reale, Anna; Ricci, Giulia; Catizone, Angela; Mariggiò, Maria A. - 01h Abstract in rivista
rivista: BIOLOGY AND LIFE SCIENCES FORUM (Basel: MDPI) pp. 7- - issn: 2673-9976 - wos: (0) - scopus: (0)

11573/1617836 - 2022 - Microgravity modifies the phenotype of fibroblast and promotes remodeling of the fibroblast–keratinocyte interaction in a 3D co-culture model
Fedeli, Valeria; Cucina, Alessandra; Dinicola, Simona; Fabrizi, Gianmarco; Catizone, Angiolina; Gesualdi, Luisa; Ceccarelli, Simona; Halim Harrath, Abdel; Alwasel, Saleh H.; Ricci, Giulia; Pedata, Paola; Bizzarri, Mariano; Monti, Noemi - 01a Articolo in rivista
rivista: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES (Basel: MDPI Center) pp. 1-22 - issn: 1422-0067 - wos: WOS:000762469000001 (8) - scopus: 2-s2.0-85124612813 (8)

11573/1688330 - 2022 - Radioresistance Mechanisms in Prostate Cancer Cell Lines Surviving Ultra-Hypo-Fractionated EBRT: Implications and Possible Clinical Applications
Sideri, Silvia; Petragnano, Francesco; Maggio, Roberto; Petrungaro, Simonetta; Catizone, Angela; Gesualdi, Luisa; De Martino, Viviana; Battafarano, Giulia; Del Fattore, Andrea; Liguoro, Domenico; De Cesaris, Paola; Filippini, Antonio; Marampon, Francesco; Riccioli, Anna - 01a Articolo in rivista
rivista: CANCERS (Basel: MDPI) pp. 5504- - issn: 2072-6694 - wos: (0) - scopus: 2-s2.0-85142513870 (0)

11573/1469783 - 2020 - The PI3K/AKT pathway is activated by HGF in NT2D1 non‐seminoma cells and has a role in the modulation of their malignant behavior
Gesualdi, L.; Leonetti, E.; Cucina, A.; Scicchitano, B. M.; Sorrentino, S.; Tarsitano, M. G.; Isidori, A.; Bizzarri, M.; Filippini, A.; Riccioli, A.; Cammarota, M.; Gigantino, V.; Ricci, G.; Catizone, A. - 01a Articolo in rivista
rivista: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES (Basel: MDPI Center) pp. 1-21 - issn: 1422-0067 - wos: WOS:000594254500001 (6) - scopus: 2-s2.0-85096459525 (6)

11573/1227713 - 2019 - C-Src recruitment is Involved in c-MET-mediated malignant behaviour of NT2D1 non-seminoma cells
Leonetti, Erica; Gesualdi, Luisa; Scheri, Katia Corano; Dinicola, Simona; Fattore, Luigi; Masiello, Maria Grazia; Cucina, Alessandra; Mancini, Rita; Bizzarri, Mariano; Ricci, Giulia; Catizone, Angela - 01a Articolo in rivista
rivista: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES (Basel: MDPI Center) pp. 1-21 - issn: 1422-0067 - wos: WOS:000459746500088 (9) - scopus: 2-s2.0-85060024879 (8)

11573/1138714 - 2018 - c-MET receptor as potential biomarker and target molecule for malignant testicular germ cell tumors
Corano Scheri, K; Leonetti, E; Laino, L; Gigantino, V; Gesualdi, L; Grammatico, P; Bizzari, M; Franco, R; Oosterhuis, Jw; Stoop, H; Looijenga, Lhj; Ricci, G; Catizone, A. - 01a Articolo in rivista
rivista: ONCOTARGET (Albany, N.Y. : Impact Journals) pp. 31842-31860 - issn: 1949-2553 - wos: (0) - scopus: 2-s2.0-85054934970 (11)

11573/1290850 - 2018 - c-Src is involved in the c-MET-mediated migrating and invading behavior of NT2D1 Embryonal Carcinoma cells.
Leonetti, E.; Gesualdi, L.; Dinicola, S.; Masiello, M. G.; Bizzarri, M.; Cucina, A.; Catizone, A.; Ricci, G. - 04f Poster
congresso: 10th European Congress of Andrology (Budapest, Hungary)
libro: 10th European Congress of Andrology - ()

11573/1173949 - 2018 - PI3K role in the c-Met-mediated migrating and invading behavior of NT2D1 non-seminoma cells
Leonetti, Erica; Gesualdi, Luisa; Dinicola, Simona; Masiello, Maria Grazia; Bizzarri, Mariano; Cucina, Alessandra; Catizone, Angiolina; Ricci, Giulia - 04f Poster
congresso: XV FISV Congress (Sapienza University of Rome)
libro: FISV - ()

11573/1017859 - 2017 - c-MET receptor: a potential biomarker for Testicular Germ Cell Tumours.
Corano Scheri, Katia; Ricci, Giulia; Leonetti, Erica; Gesualdi, L.; Oosterhuis, J. W.; Stoop, J.; Looijenga, Eduard Jacob Neven; Catizone, A.; L. H. J., - 04f Poster
congresso: 10th Network of Young Researcher in Andrology meeting (Brussels, Belgium)
libro: 10th Network of Young Researcher in Andrology meeting - ()

11573/1017856 - 2017 - Microgravity promotes gap junctional contact formation in TCam-2 seminoma cells grown in low adhesion as embryoid bodies.
Leonetti, Erica; Corano Scheri, Katia; Gesualdi, Luisa; Cammarota, Marcella; Schiraldi, Chiara; Bizzarri, Mariano; Catizone, Angiolina; Ricci, Giulia - 04f Poster
congresso: ABCD National Congress 2017 (Bologna, Italy)
libro: ABCD National Congress 2017 - ()

11573/906291 - 2016 - HGF/c-Met pathway in seminoma and non-seminoma cell lines: role in cell invasion.
Corano Scheri, Katia; Leonetti, Erica; Gesualdi, L.; Ricci, G.; Catizone, Angiolina - 04f Poster
congresso: VII BeMM Symposium (Rome, Italy)
libro: VII BeMM Symposium - ()

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