HDAC Inhibition Induces Cell Cycle Arrest and Mesenchymal-Epithelial Transition in a Novel Pleural-Effusion Derived Uterine Carcinosarcoma Cell Line
Authors: Paul Stockhammer, Özlem Okumus, Luca Hegedus, Dominika Rittler, Till Ploenes, Thomas Herold, Stavros Kalbourtzis, Agnes Bankfalvi, Antje Sucker, Rainer Kimmig, Clemens Aigner, Balazs Hegedus
Journal: Pathol Oncol Res (2021)
Keywords: arid1a, hdac inhibition, epithelial-mesenchymal transition, mesenchymal-epithelial transition, targeted therapy, uterine carcinosarcoma
MeSH terms: Antineoplastic Combined Chemotherapy Protocols / therapeutic use, Carcinosarcoma / pathology, Cell Cycle Checkpoints, Epithelial-Mesenchymal Transition, Histone Deacetylases / chemistry, Pleural Effusion, Malignant / pathology, Uterine Neoplasms / pathology, Case Reports, Biomarkers, Tumor / genetics, Carcinosarcoma / drug therapy, Carcinosarcoma / metabolism, Cisplatin / administration & dosage, Female, Gene Expression Regulation, Neoplastic, Humans, Middle Aged, Mutation, Paclitaxel / administration & dosage, Phthalazines / administration & dosage, Piperazines / administration & dosage, Pleural Effusion, Malignant / drug therapy, Pleural Effusion, Malignant / metabolism, Prognosis, Pyrazoles / administration & dosage, Quinolines / administration & dosage, Tumor Cells, Cultured, Uterine Neoplasms / drug therapy, Uterine Neoplasms / metabolism, Vorinostat / administration & dosage, Biomarkers, Tumor, Phthalazines, Piperazines, Pyrazoles, Quinolines, Vorinostat, LY-2157299, Histone Deacetylases, Paclitaxel, Cisplatin, olaparib

Objective: 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. Methods: 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 in vitro sensitivity to different standard and novel treatments. E-cadherin, β-catenin and pSMAD2 expressions were measured by immunoblot. Results: 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 KRAS, PIK3CA, PTEN and ARID1A. 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. Conclusions: 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.