Abstract
CIC-DUX4 sarcoma (CDS) is a group of rare, mesenchymal, small round cell tumours that harbour the unique CIC-DUX4 translocation, which causes aberrant gene expression. CDS exhibits an aggressive course and poor clinical outcome, thus novel therapeutic approaches are needed for CDS treatment. Although patient-derived cancer models are an essential modality to develop novel therapies, none currently exist for CDS. Thus, the present study successfully established CDS patient-derived xenografts and subsequently generated two CDS cell lines from the grafted tumours. Notably, xenografts were histologically similar to the original patient tumour, and the expression of typical biomarkers was confirmed in the xenografts and cell lines. Moreover, the xenograft tumours and cell lines displayed high Src kinase activities, as assessed by peptide-based tyrosine kinase array. Upon screening 119 FDA-approved anti-cancer drugs, we found that only actinomycine D and doxorubicin were effectively suppress the proliferation among the drugs for standard therapy for Ewing sarcoma. However, we identified molecular targeting reagents, such as bortezomib and crizotinib that markedly suppressed the growth of CDS cells. Our models will be useful modalities to develop novel therapeutic strategies against CDS.
Highlights
CIC-DUX4 sarcoma (CDS) is a recently characterized subset of high-grade sarcoma that accounts for the majority of Ewing-like small round cell sarcomas[1]
CIC encodes a transcriptional repressor with a high-mobility group (HMG)-box containing DNA-binding domain that functions as a primary downstream sensor of receptor tyrosine kinase (RTK)/extracellular signal-regulated kinase (ERK) pathway activity[13,14,15,16,17]
Fluorescence in situ hybridization (FISH) experiments indicated that most of the tumour cells harboured split green and orange signals, suggesting the presence of CIC gene rearrangement (Fig. 1f), which was confirmed by reverse transcription (RT)-PCR
Summary
CIC-DUX4 sarcoma (CDS) is a recently characterized subset of high-grade sarcoma that accounts for the majority of Ewing-like small round cell sarcomas[1]. The deduced chimeric CIC–DUX4 protein exhibits strong transcriptional activity to induce a unique gene expression profile[4], which considerably differs from that of Ewing sarcoma[21]. Beside these analyses, no study has characterised the detailed biological features of CDS tumours or the possibility of targeting the CIC–DUX4 fusion protein for CDS therapy. Patient-derived cancer models are an essential modality to understand molecular carcinogenesis and develop novel therapeutic strategies[22]. We developed patient-derived cancer models of CDS, characterised their histological and biomolecular features, and investigated the growth inhibitory effects of anti-cancer drugs on CDS cells. This is the first report on the establishment of patient-derived cancer models of CDS, and has the potential to facilitate CDS research
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