TY  - JOUR
AU  - Schwab, Hannah
AU  - Kerkhoff, Maximilian
AU  - Plaumann, Pauline
AU  - Collaud, Stéphane
AU  - Dirksen, Uta
AU  - Theegarten, Dirk
AU  - Herold, Thomas
AU  - Kalbourtzis, Stavros
AU  - Bölükbas, Servet
AU  - Hegedüs, Balazs
AU  - Hegedüs, Luca
TI  - Characterization of a novel sarcoma cell line with an EWSR1::POU2AF3 fusion.
JO  - Pathology & oncology research
VL  - 31
SN  - 1219-4956
CY  - Heidelberg
PB  - Springer
M1  - DKFZ-2025-00635
SP  - 1611986
PY  - 2025
AB  - Sarcomas with an EWSR1::POU2AF3(COLCA2) fusion are a very recently described entity of preferentially sinonasal origin and with undifferentiated round/spindle cell morphology. We established a novel cell line (PF1095) carrying a EWSR1::POU2AF3 fusion from the malignant pleural effusion of a 25-year-old sarcoma patient. The patient was first diagnosed with poorly differentiated neuroendocrine carcinoma based on tumor cell morphology and positivity to markers such as EMA, synaptophysin, and CD56. Later, the EWSR1 translocation was identified in the tumor cells with unknown partners and the patient received chemotherapy according to the Ewing 2008 protocol in combination with surgery and proton beam radiotherapy. At the time of cell line establishment, the disease progressed to pleural sarcomatosis with pleural effusion. In the cell line, we identified POU2AF3 as a fusion partner of EWSR1 and a TP53 frameshift deletion. Next, we determined the sensitivity of PF1095 cells to the currently approved chemotherapies in comparison to two conventional Ewing sarcoma lines (EW-7 and MHH-ES1) with the two most frequent EWSR::FLI1 fusions. Finally, we tested potential new combination therapies. We performed cell viability, proliferation, and cell cycle assays. We found that the proliferation rate of PF1095 cells was much slower than the EWSR1::FLI1 fusion lines and they also had a lower sensitivity to both irinotecan and doxorubicin treatment. Expression level of SLFN11, a predictor of sensitivity to DNA damaging agents, was also lower in PF1095 cells. Combination treatment with the PARP inhibitors olaparib and irinotecan or doxorubicin synergistically reduced cell viability and induced cell death and cell cycle arrest. This unique cell model provides an opportunity to test therapeutic approaches preclinically for this novel and aggressive sarcoma entity.
KW  - Humans
KW  - Oncogene Proteins, Fusion: genetics
KW  - RNA-Binding Protein EWS: genetics
KW  - Adult
KW  - Sarcoma: genetics
KW  - Sarcoma: pathology
KW  - Cell Line, Tumor
KW  - Cell Proliferation
KW  - Male
KW  - EWSR1 (Other)
KW  - POU2AF3 (Other)
KW  - chemotherapy (Other)
KW  - patient derived cell line (Other)
KW  - sarcoma (Other)
KW  - Oncogene Proteins, Fusion (NLM Chemicals)
KW  - RNA-Binding Protein EWS (NLM Chemicals)
KW  - EWSR1 protein, human (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:40134582
C2  - pmc:PMC11932835
DO  - DOI:10.3389/pore.2025.1611986
UR  - https://inrepo02.dkfz.de/record/300144
ER  -