Magrath Justin W, Kang Hong-Jun, Hartono Alifiani, Espinosa-Cotton Madelyn, Somwar Romel, Ladanyi Marc, Cheung Nai-Kong V, Lee Sean B
Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA, United States.
Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, United States.
Front Cell Dev Biol. 2022 Nov 25;10:1048709. doi: 10.3389/fcell.2022.1048709. eCollection 2022.
Desmoplastic Small Round Cell Tumor (DSRCT) is a rare and aggressive pediatric cancer driven by the fusion oncogene. Combinations of chemotherapy, radiation and surgery are not curative, and the 5-years survival rate is less than 25%. One potential explanation for refractoriness is the existence of a cancer stem cell (CSC) subpopulation able escape current treatment modalities. However, no study to-date has examined the role of CSCs in DSRCT or established culture conditions to model this subpopulation. In this study, we investigated the role of stemness markers in DSRCT survival and metastasis, finding that elevated levels of and are associated with worse survival in sarcoma patients and are elevated in metastatic DSRCT tumors. We further develop the first DSRCT CSC model which forms tumorspheres, expresses increased levels of stemness markers (, , , and ), and resists doxorubicin chemotherapy treatment. This model is an important addition to the DSRCT tool kit and will enable investigation of this critical DSRCT subpopulation. Despite lower sensitivity to chemotherapy, the DSRCT CSC model remained sensitive to knockdown of the fusion protein, suggesting that future therapies directed against this oncogenic driver have the potential to treat both DSRCT bulk tumor and CSCs.
促结缔组织增生性小圆细胞肿瘤（DSRCT）是一种由融合致癌基因驱动的罕见且侵袭性强的儿童癌症。化疗、放疗和手术联合治疗无法治愈该疾病，其5年生存率低于25%。治疗难治性的一个潜在解释是存在能够逃避当前治疗方式的癌症干细胞（CSC）亚群。然而，迄今为止尚无研究探讨CSC在DSRCT中的作用，也未建立模拟该亚群的培养条件。在本研究中，我们调查了干性标志物在DSRCT生存和转移中的作用，发现其水平升高与肉瘤患者较差的生存率相关，且在转移性DSRCT肿瘤中升高。我们进一步建立了首个DSRCT CSC模型，该模型可形成肿瘤球，表达升高水平的干性标志物（、、、和），并对阿霉素化疗产生抗性。该模型是DSRCT工具库的重要补充，将有助于对这个关键的DSRCT亚群进行研究。尽管对化疗敏感性较低，但DSRCT CSC模型对融合蛋白的敲低仍敏感，这表明未来针对这种致癌驱动因素的疗法有可能治疗DSRCT实体瘤和CSC。
