AUTHOR=Stockhammer Paul , Okumus Özlem , Hegedus Luca , Rittler Dominika , Ploenes Till , Herold Thomas , Kalbourtzis Stavros , Bankfalvi Agnes , Sucker Antje , Kimmig Rainer , Aigner Clemens , Hegedus Balazs 

TITLE=HDAC Inhibition Induces Cell Cycle Arrest and Mesenchymal-Epithelial Transition in a Novel Pleural-Effusion Derived Uterine Carcinosarcoma Cell Line

JOURNAL=Pathology and Oncology Research

VOLUME=27

YEAR=2021

URL=https://www.por-journal.com/journals/pathology-and-oncology-research/articles/10.3389/pore.2021.636088

DOI=10.3389/pore.2021.636088

ISSN=1532-2807

ABSTRACT=<p><bold>Objective:</bold> Uterine carcinosarcoma (UCS) is a rare but highly aggressive malignancy with biphasic growth pattern. This morphology can be attributed to epithelial-mesenchymal transition (EMT) that often associates with tumor invasion and metastasis. Accordingly, we analyzed a novel patient-derived preclinical model to explore whether EMT is a potential target in UCS.</p><p><bold>Methods:</bold> A novel UCS cell line (PF338) was established from the malignant pleural effusion of a 59-year-old patient at time of disease progression. Immunohistochemistry was performed in primary and metastatic tumor lesions. Oncogenic mutations were identified by next-generation sequencing. Viability assays and cell cycle analyses were used to test <italic>in vitro</italic> sensitivity to different standard and novel treatments. E-cadherin, β-catenin and pSMAD2 expressions were measured by immunoblot.</p><p><bold>Results:</bold> Whereas immunohistochemistry of the metastatic tumor showed a predominantly sarcomatous vimentin positive tumor that has lost E-cadherin expression, PF338 cells demonstrated biphasic growth and carried mutations in <italic>KRAS</italic>, <italic>PIK3CA</italic>, <italic>PTEN</italic> and <italic>ARID1A</italic>. PF338 tumor cells were resistant to MEK- and TGF-β signaling-inhibition but sensitive to PIK3CA- and PARP-inhibition and first-line chemotherapeutics. Strikingly, histone deacetylase (HDAC) inhibition markedly reduced cell viability by inducing a dose-dependent G0/1 arrest and led to mesenchymal-epithelial transition as evidenced by morphological change and increased E-cadherin and β-catenin expression.</p><p><bold>Conclusions:</bold> Our data suggest that HDAC inhibition is effective in a novel UCS cell line by interfering with both viability and differentiation. These findings emphasize the dynamic manner of EMT/MET and epigenetics and the importance of molecular profiling to pave the way for novel therapies in UCS.</p>