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, beta-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-beta 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 beta-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.
