Dottoressa di ricerca

ciclo: XXXIV

relatore: Raffaele Strippoli
co-supervisore: Raffaele Strippoli

Titolo della tesi: 1/2 HDACs inhibition impacts mesenchymal-like mesothelial cells/ovary cancer adhesive interactions inhibiting α5β1 Integrin activation.

Peritoneal metastasis accounts for 85% of all epithelial ovarian carcinoma (EOC) metastases and is a main route from other primary tumors emerging in the peritoneal cavity, such as gastrointestinal cancers. Peritoneal metastasis is a multistep process requiring firstly the establishment of adhesive interactions between cancer cells and the peritoneal membrane. Although it has been demonstrated that the acquisition of EMT-like features by peritoneum mesothelial cells (MCs), a process known as mesothelial to mesenchymal transition (MMT), facilitates the metastatic process, this process of ‘peritoneal education’ by cancer cells has been incompletely studied. Here, we analyzed the epigenetic regulation of MC-EOC adesion, focusing on the plasticity of the MC monolayer. Published evidence demonstrates the ability of HDAC inhibition in promoting the reversal towards an epithelial-like phenotype in MCs. Here, we found that treatment of fibrotic MCs and platinum-resistant EOC lines with MS-275, an HDAC1-3 pharmacological inhibitor, significantly limits MCs/EOC adhesion. This process was reproduced by HDAC1 genetic silencing. When analyzing molecular mechanisms underlying, we focused on the expression of ECM molecules and in the analysis of Integrin subunits responsible for MCs/EOC adhesion. Proteomic analysis revealed a number of molecular pathways altered upon treatment of MCs with MS-275, including ECM molecules, adhesion receptors and actin cytoskeleton regulators. Experiments of genetic silencing, use of specific pharmacological inhibitors and inhibitory antibodies led us to draw two possibly integrating mechanisms: i. downregulated metalloproteinase (MMP) expression leading to abnormal Fibronectin (FN-1) fiber formation and provoking defective adhesion; ii. alteration of actin cytoskeleton polymerization due to downregulation of actin regulator TALIN-1 leading to defective α5β1 Integrin activation. These studies focusing on the epigenetic regulation of MCs plasticity, provide a new mechanism of action of HDAC-1 inhibition and open to a new perspective for EOC therapeutic intervention.

Produzione scientifica

11573/1700487 - 2024 - HDAC1/2 control mesothelium/ovarian cancer adhesive interactions impacting on Talin-1-α5β1-integrin-mediated actin cytoskeleton and extracellular matrix protein remodeling
Terri, Michela; Sandoval, Pilar; Bontempi, Giulio; Montaldo, Claudia; Tomero-Sanz, Henar; De Turris, Valeria; Trionfetti, Flavia; Pascual-Antón, Lucía; Clares-Pedrero, Irene; Battistelli, Cecilia; Valente, Sergio; Zwergel, Clemens; Mai, Antonello; Rosanò, Laura; Del Pozo, Miguel Ángel; Sánchez-Álvarez, Miguel; Cabañas, Carlos; Tripodi, Marco; López-Cabrera, Manuel; Strippoli, Raffaele - 01a Articolo in rivista
rivista: JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH (London : BioMed Central) pp. - - issn: 1756-9966 - wos: (0) - scopus: (0)

Trionfetti, Flavia; Marchant, Vanessa; Terri, Michela; Bontempi, Giulio; Domenici, Alessandro; Mene, Paolo; Ruiz-Ortega, Marta; Strippoli, Raffaele - 01h Abstract in rivista
rivista: NEPHROLOGY DIALYSIS TRANSPLANTATION (Oxford: Oxford University Press.) pp. 1164-1164 - issn: 1460-2385 - wos: WOS:001022961100156 (0) - scopus: (0)

11573/1659806 - 2022 - Restoration of WT1/miR-769-5p axis by HDAC1 inhibition promotes MMT reversal in mesenchymal-like mesothelial cells
Bontempi, Giulio; Terri, Michela; Garbo, Sabrina; Montaldo, Claudia; Mariotti, Davide; Bordoni, Veronica; Valente, Sergio; Zwergel, Clemens; Mai, Antonello; Marchetti, Alessandra; Domenici, Alessandro; Menè, Paolo; Battistelli, Cecilia; Tripodi, Marco; Strippoli, Raffaele - 01a Articolo in rivista
rivista: CELL DEATH & DISEASE (Nature Group) pp. 965- - issn: 2041-4889 - wos: WOS:000885083500004 (6) - scopus: 2-s2.0-85142134241 (9)

11573/1612876 - 2022 - Exposure to b‐LED light while exerting antimicrobial activity on Gram‐negative and ‐positive bacteria promotes transient EMT‐like changes and growth arrest in keratinocytes
Terri, M.; Mancianti, N.; Trionfetti, F.; Casciaro, B.; De Turris, V.; Raponi, G.; Bontempi, G.; Montaldo, C.; Domenici, A.; Mene', P.; Mangoni, M. L.; Strippoli, R. - 01a Articolo in rivista
rivista: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES (Basel (Matthaeustrasse 11) : Molecular Diversity Preservation International MDPI) pp. - - issn: 1661-6596 - wos: WOS:000755651500001 (1) - scopus: 2-s2.0-85124280849 (2)

11573/1610922 - 2021 - Pleural mesothelial cells modulate the inflammatory/profibrotic response during SARS-CoV-2 infection
Matusali, Giulia; Trionfetti, Flavia; Bordoni, Veronica; Nardacci, Roberta; Falasca, Laura; Colombo, Daniele; Terri, Michela; Montaldo, Claudia; Castilletti, Concetta; Mariotti, Davide; Del Nonno, Franca; Capobianchi, Maria Rosaria; Agrati, Chiara; Tripodi, Marco; Strippoli, Raffaele - 01a Articolo in rivista
rivista: FRONTIERS IN MOLECULAR BIOSCIENCES (Lausanne : Frontiers Media S.A., 2014-) pp. - - issn: 2296-889X - wos: WOS:000893554700001 (4) - scopus: 2-s2.0-85121011510 (6)

11573/1571274 - 2021 - Fibrogenic signals persist in DAA-treated HCV patients after sustained virological response
Montaldo, Claudia; Terri, Michela; Riccioni, Veronica; Battistelli, Cecilia; Bordoni, Veronica; D'offizi, Gianpiero; Prado, Maria Giulia; Trionfetti, Flavia; Vescovo, Tiziana; Tartaglia, Eleonora; Strippoli, Raffaele; Agrati, Chiara; Tripodi, Marco - 01a Articolo in rivista
rivista: JOURNAL OF HEPATOLOGY (Blackwell Munksgaard:PO Box 2148, Periodicals Department, DK-1016 Copenhagen K Denmark:011 45 33 755913, EMAIL: agentservices@oxon.blackwellpublishing.com, INTERNET: http://www.blackwellmunksgaard.com, Fax: 011 45 77 333377) pp. 1301-1311 - issn: 0168-8278 - wos: WOS:000727375100007 (13) - scopus: 2-s2.0-85114987180 (20)

11573/1550677 - 2021 - Mechanisms of peritoneal fibrosis: focus on immune cells-peritoneal stroma interactions
Terri, Michela; Trionfetti, Flavia; Montaldo, Claudia; Cordani, Marco; Tripodi, Marco; Lopez-Cabrera, Manuel; Strippoli, Raffaele - 01g Articolo di rassegna (Review)
rivista: FRONTIERS IN IMMUNOLOGY (Lausanne : Frontiers Research Foundation, 2010-) pp. - - issn: 1664-3224 - wos: WOS:000639137900001 (44) - scopus: 2-s2.0-85104013369 (44)

11573/1435589 - 2020 - Caveolin1 and YAP drive mechanically induced mesothelial to mesenchymal transition and fibrosis
Strippoli, Raffaele; Sandoval, Pilar; Moreno-Vicente, Roberto; Rossi, Lucia; Battistelli, Cecilia; Terri, Michela; Pascual-Antón, Lucía; Loureiro, Marta; Matteini, Francesca; Calvo, Enrique; 9, José Antonio Jiménez-Heffernan; José Gómez 10, Manuel; Jiménez-Jiménez, Victor; Sánchez-Cabo, Fátima; Vázquez, Jesús; Tripodi, Marco; López-Cabrera, Manuel; Ángel Del Pozo, Miguel - 01a Articolo in rivista
rivista: CELL DEATH & DISEASE (Nature Group) pp. - - issn: 2041-4889 - wos: WOS:000579809200002 (32) - scopus: 2-s2.0-85089528848 (32)

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