dc.contributor.author | Terri, Michela | |
dc.contributor.author | Sandoval, Pilar | |
dc.contributor.author | Bontempi, Giulio | |
dc.contributor.author | Montaldo, Claudia | |
dc.contributor.author | Tomero-Sanz, Henar | |
dc.contributor.author | de Turris, Valeria | |
dc.contributor.author | Trionfetti, Flavia | |
dc.contributor.author | Pascual-Antón, Lucía | |
dc.contributor.author | Clares-Pedrero, Irene | |
dc.contributor.author | Battistelli, Cecilia | |
dc.contributor.author | Valente, Sergio | |
dc.contributor.author | Zwergel, Clemens | |
dc.contributor.author | Mai, Antonello | |
dc.contributor.author | Rosanò, Laura | |
dc.contributor.author | del Pozo, Miguel Angel | |
dc.contributor.author | Sánchez-Álvarez, Miguel | |
dc.contributor.author | Cabañas, Carlos | |
dc.contributor.author | Tripodi, Marco | |
dc.contributor.author | López-Cabrera, Manuel | |
dc.contributor.author | Strippoli, Raffaele | |
dc.date.accessioned | 2024-07-09T09:41:03Z | |
dc.date.available | 2024-07-09T09:41:03Z | |
dc.date.issued | 2024-01-23 | |
dc.identifier.citation | J Exp Clin Cancer Res. 2024 Jan 23;43(1):27. | es_ES |
dc.identifier.uri | http://hdl.handle.net/20.500.12105/20318 | |
dc.description.abstract | BACKGROUND
Peritoneal metastasis, which accounts for 85% of all epithelial ovarian carcinoma (EOC) metastases, is a multistep process that requires the establishment of adhesive interactions between cancer cells and the peritoneal membrane. Interrelations between EOC and the mesothelial stroma are critical to facilitate the metastatic process. No data is available so far on the impact of histone acetylation/deacetylation, a potentially relevant mechanism governing EOC metastasis, on mesothelial cells (MCs)-mediated adhesion.
METHODS
Static adhesion and peritoneal clearance experiments were performed pretreating mesenchymal-like MCs and platinum-sensitive/resistant EOC cell lines with MS-275-a Histone deacetylase (HDAC)1-3 pharmacological inhibitor currently used in combination trials. Results were acquired by confocal microscopy and were analyzed with an automated Opera software. The role of HDAC1/2 was validated by genetic silencing. The role of α4-, α5-α1 Integrins and Fibronectin-1 was validated using specific monoclonal antibodies. Quantitative proteomic analysis was performed on primary MCs pretreated with MS-275. Decellularized matrices were generated from either MS-275-exposed or untreated cells to study Fibronectin-1 extracellular secretion. The effect of MS-275 on β1 integrin activity was assessed using specific monoclonal antibodies. The role of Talin-1 in MCs/EOC adhesion was analyzed by genetic silencing. Talin-1 ectopic expression was validated as a rescue tool from MS-275-induced phenotype. The in vivo effect of MS-275-induced MC remodeling was validated in a mouse model of peritoneal EOC dissemination.
RESULTS
Treatment of MCs with non-cytotoxic concentrations of MS-275 caused a consistent reduction of EOC adhesion. Proteomic analysis revealed several pathways altered upon MC treatment with MS-275, including ECM deposition/remodeling, adhesion receptors and actin cytoskeleton regulators. HDAC1/2 inhibition hampered actin cytoskeleton polymerization by downregulating actin regulators including Talin-1, impairing β1 integrin activation, and leading to abnormal extracellular secretion and distribution of Fibronectin-1. Talin-1 ectopic expression rescued EOC adhesion to MS-275-treated MCs. In an experimental mouse model of metastatic EOC, MS-275 limited tumor invasion, Fibronectin-1 secretion and the sub-mesothelial accumulation of MC-derived carcinoma-associated fibroblasts.
CONCLUSION
Our study unveils a direct impact of HDAC-1/2 in the regulation of MC/EOC adhesion and highlights the regulation of MC plasticity by epigenetic inhibition as a potential target for therapeutic intervention in EOC peritoneal metastasis. | es_ES |
dc.description.sponsorship | This research was funded by: AIRC (Associazione Italiana per la Ricerca sul
Cancro) (IG26172) and Ateneo Sapienza Project 2020 (RG120172B8E53D03) to
S.V; by FISR2019_00374 MeDyCa to AM; by FSE REACT-EU within the program
PON “Research and Innovation” 2014–2020, Action IV.6 “Contratti di ricerca
su tematiche Green” to CZ; by SEED PNR 2021 to C.B.; by AIRC IG26290, by
Sapienza University of Rome (RG11916B6A9C42C7) to M. Tr and by Ministry for
Health of Italy (Ricerca Corrente), by AIRC (IG21372 to LR), by PRIN 2022 PNRR
(P2022XZKBM) fnanced by the European Union - NextGenerationEU», to RS.
This work was also supported by grants (PID2019-110132RB-I00/AEI/https://
doi.org/10.13039/501100011033 and PID2022-142796OB-I00/AEI/https://
doi.org/10.13039/501100011033)) from the Spanish Ministry of Science and
Innovation/Fondo Europeo de Desarrollo Regional (MICIN/FEDER) to ML-C and
by a grant PID2021-123199OB-I00 from the Spanish Ministry of Science and
Innovation/Fondo Europeo de Desarrollo Regional (MICIN/FEDER) to CC.
MAdP is recipient/co-recipient of funding from the Spanish Ministry of Sci‑
ence and Innovation (MCIN) (refs. SAF2017–83130-R cofunded by “ERDF A way
of making Europe”, PID2020-118658RB-I00, PDC2021–121572-100 cofunded
by “European Union NextGeneration EU/PRTR”), Asociación Española Contra
el Cáncer foundation (AECC; PROYE20089DELP); La Marató TV3 foundation
(201936–30-31), Obra social La Caixa (AtheroConvergence, HR20–00075) and
Comunidad Autónoma de Madrid/FEDER (Tec4Bio consortium, ref. S2018/
NMT¬4443). MS-A is recipient of a Ramón y Cajal research contract from MCIN
(RYC2020–029690-I) and research grant PID2021-128106NA-I00, both from
Spanish MCIN.
The CNIC is supported by the Instituto de Salud Carlos III (ISCIII), the Ministerio
de Ciencia e Innovación (MCIN) and the Pro CNIC Foundation), and is a Severo
Ochoa Center of Excellence (grant CEX2020–001041-S funded by MICIN/
AEI/https://doi.org/10.13039/501100011033). | es_ES |
dc.language.iso | eng | es_ES |
dc.publisher | BioMed Central (BMC) | es_ES |
dc.type.hasVersion | VoR | es_ES |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | * |
dc.subject.mesh | Benzamides | es_ES |
dc.subject.mesh | Carcinoma, Ovarian Epithelial | es_ES |
dc.subject.mesh | Histone Deacetylase 1 | es_ES |
dc.subject.mesh | Ovarian Neoplasms | es_ES |
dc.subject.mesh | Peritoneal Neoplasms | es_ES |
dc.subject.mesh | Histone Deacetylase 2 | es_ES |
dc.subject.mesh | Cell Adhesion | es_ES |
dc.subject.mesh | Animals | es_ES |
dc.subject.mesh | Female | es_ES |
dc.subject.mesh | Humans | es_ES |
dc.subject.mesh | Mice | es_ES |
dc.subject.mesh | Actin Cytoskeleton | es_ES |
dc.subject.mesh | Antibodies, Monoclonal | es_ES |
dc.subject.mesh | Epithelium | es_ES |
dc.subject.mesh | Extracellular Matrix Proteins | es_ES |
dc.subject.mesh | Fibronectins | es_ES |
dc.subject.mesh | Integrin alpha5 | es_ES |
dc.subject.mesh | Integrin beta1 | es_ES |
dc.subject.mesh | Proteomics | es_ES |
dc.subject.mesh | Pyridines | es_ES |
dc.subject.mesh | Talin | es_ES |
dc.title | HDAC1/2 control mesothelium/ovarian cancer adhesive interactions impacting on Talin-1-α5β1-integrin-mediated actin cytoskeleton and extracellular matrix protein remodeling. | es_ES |
dc.type | journal article | es_ES |
dc.rights.license | Atribución 4.0 Internacional | * |
dc.identifier.pubmedID | 38254102 | es_ES |
dc.format.volume | 43 | es_ES |
dc.format.number | 1 | es_ES |
dc.format.page | 27 | es_ES |
dc.identifier.doi | 10.1186/s13046-023-02930-8 | es_ES |
dc.contributor.funder | Unión Europea. Comisión Europea. NextGenerationEU | es_ES |
dc.contributor.funder | Ministerio de Ciencia e Innovación (España) | es_ES |
dc.contributor.funder | Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF) | es_ES |
dc.contributor.funder | Asociación Española Contra el Cáncer | es_ES |
dc.contributor.funder | Fundación La Marató TV3 | es_ES |
dc.contributor.funder | Comunidad de Madrid (España) | es_ES |
dc.contributor.funder | Ministerio de Ciencia e Innovación. Centro de Excelencia Severo Ochoa (España) | es_ES |
dc.description.peerreviewed | Sí | es_ES |
dc.identifier.e-issn | 1756-9966 | es_ES |
dc.relation.publisherversion | 10.1186/s13046-023-02930-8 | es_ES |
dc.identifier.journal | Journal of experimental & clinical cancer research : CR | es_ES |
dc.repisalud.orgCNIC | CNIC::Grupos de investigación::Mecanoadaptación y Biología de Caveolas | es_ES |
dc.repisalud.institucion | CNIC | es_ES |
dc.rights.accessRights | open access | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/PID2019-110132RB-I00 | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/PID2022-142796OB-I00 | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/PID2021-123199OB-I00 | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/SAF2017–83130-R | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/PID2020-118658RB-I00 | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/PDC2021–121572-100 | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/PROYE20089DELP | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/201936–30-31 | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/HR20–00075 | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/S2018/NMT/4443 | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/RYC2020–029690-I | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/PID2021-128106NA-I00 | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/10.13039/501100011033/CEX2020–001041-S | es_ES |