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Journal of Experimental & Clinical Cancer Research
Published in: Journal of Experimental & Clinical Cancer Research 1/2024

Open Access 01-12-2024 | Ovarian Cancer | Research

HDAC1/2 control mesothelium/ovarian cancer adhesive interactions impacting on Talin-1-α5β1-integrin-mediated actin cytoskeleton and extracellular matrix protein remodeling

Authors: Michela Terri, Pilar Sandoval, Giulio Bontempi, Claudia Montaldo, Henar Tomero-Sanz, Valeria de Turris, Flavia Trionfetti, Lucía Pascual-Antón, Irene Clares-Pedrero, Cecilia Battistelli, Sergio Valente, Clemens Zwergel, Antonello Mai, Laura Rosanò, Miguel Ángel del Pozo, Miguel Sánchez-Álvarez, Carlos Cabañas, Marco Tripodi, Manuel López-Cabrera, Raffaele Strippoli

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2024

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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.
Appendix
Available only for authorised users
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Metadata
Title
HDAC1/2 control mesothelium/ovarian cancer adhesive interactions impacting on Talin-1-α5β1-integrin-mediated actin cytoskeleton and extracellular matrix protein remodeling
Authors
Michela Terri
Pilar Sandoval
Giulio Bontempi
Claudia Montaldo
Henar Tomero-Sanz
Valeria de Turris
Flavia Trionfetti
Lucía Pascual-Antón
Irene Clares-Pedrero
Cecilia Battistelli
Sergio Valente
Clemens Zwergel
Antonello Mai
Laura Rosanò
Miguel Ángel del Pozo
Miguel Sánchez-Álvarez
Carlos Cabañas
Marco Tripodi
Manuel López-Cabrera
Raffaele Strippoli
Publication date
01-12-2024
Publisher
BioMed Central
Published in
Journal of Experimental & Clinical Cancer Research / Issue 1/2024
Electronic ISSN: 1756-9966
DOI
https://doi.org/10.1186/s13046-023-02930-8

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