Epithelioid peritoneal mesothelioma: A hybrid phenotype within a mesenchymal-epithelial/epithelial-mesenchymal transition framework

Fabio Bozzi, Silvia Brich, Gian Paolo Dagrada, Tiziana Negri, Elena Conca, Barbara Cortelazzi, Antonino Belfiore, Federica Perrone, Ambra Vittoria Gualeni, A. Gloghini, Antonello Cabras, Monica Brenca, Roberta Maestro, Nadia Zaffaroni, Paolo Giovanni Casali, Rossella Bertulli, Marcello Deraco, Silvana Pilotti

Research output: Contribution to journalArticle

Abstract

The aim of this study was to reconsider the biological characteristics of epithelioid malignant peritoneal mesothelioma (E-MpM) in the light of new concepts about epithelial mesenchymal transition and mesenchymal epithelial reverse transition (EMT/MErT) and the role of epigenetic reprogramming in this context. To this end we profiled surgical specimens and derived cells cultures by a number of complementary approaches i.e. immunohistochemistry, immunofluorescence, in situ hybridization, biochemistry, pluripotent stem cell arrays, treatments with cytokines, growth factors and specific inhibitors. The analyses of the surgical specimens showed that i) EZH2 is expressed throughout the spectrum of MpM, ii) that E-MpM (including the high-grade undifferentiated form) are characterised by c-MYC and miRNA 17-5p expression, and iii) that progression to sarcomatoid MpM is dictated by EMT regulators. They also showed that E-MpM expressed c-MET and are enriched in E- and P-cadherins- and VEGFR2-expressing CSCs, thus strongly supporting a role for MErT reprogramming in endowing E-MpM tumour cells with stemness and plasticity, and hence with a drug resistant phenotype. The cell culture-based experiments confirmed the stemness traits and plasticity of E-MpM, and support the view that EZH2 is a druggable target in this tumor.

Original languageEnglish
Pages (from-to)75503-75517
Number of pages15
JournalOncotarget
Volume7
Issue number46
DOIs
Publication statusPublished - 2016

Keywords

  • Malignant peritoneal mesothelioma
  • MErT
  • MET

ASJC Scopus subject areas

  • Oncology

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    Bozzi, F., Brich, S., Dagrada, G. P., Negri, T., Conca, E., Cortelazzi, B., Belfiore, A., Perrone, F., Gualeni, A. V., Gloghini, A., Cabras, A., Brenca, M., Maestro, R., Zaffaroni, N., Casali, P. G., Bertulli, R., Deraco, M., & Pilotti, S. (2016). Epithelioid peritoneal mesothelioma: A hybrid phenotype within a mesenchymal-epithelial/epithelial-mesenchymal transition framework. Oncotarget, 7(46), 75503-75517. https://doi.org/10.18632/oncotarget.12262