Dawson Lucy E, D'Agostino Luca, Hakim Abraham A, Lackman Richard D, Brown Spencer A, Sensenig Richard B, Antonello Zeus A, Kuzin Igor I
Cooper University Hospital, Camden, NJ, USA.
Cooper Medical School of Rowan University, Camden, NJ, USA.
Sarcoma. 2020 Mar 26;2020:8647981. doi: 10.1155/2020/8647981. eCollection 2020.
Rhabdomyosarcoma (RMS) and rhabdoid tumors (RT) are rare soft-tissue malignancies with the highest incidence in infants, children, and adolescents. Advanced, recurrent, and/or metastatic RMS and RT exhibit poor response to treatment. One of the main mechanisms behind resistance to treatment is believed to be intratumoral heterogeneity. In this study, we investigated the myogenic determination factor 1 (MYOD1) and Noggin (NOG) markers in an embryonal RMS (ERMS) cell line and an RT cell line and the differential response of the MYOD1 and NOG expressing subpopulations to chemotherapy. Importantly, we found that these markers together identify a subpopulation of cells (MYOD1+ NOG+ cells) with primary resistance to Vincristine and Doxorubicin, two commonly used chemotherapies for ERMS and RT. The chemoresistant MYOD1+ NOG+ cells express markers of undifferentiated cells such as myogenin and ID1. Combination of Vincristine with TPA/GSK126, a drug combination shown to induce differentiation of RMS cell lines, is able to partially overcome MYOD1/NOG cells chemoresistance.
横纹肌肉瘤（RMS）和横纹肌样瘤（RT）是罕见的软组织恶性肿瘤，在婴儿、儿童和青少年中发病率最高。晚期、复发性和/或转移性RMS和RT对治疗反应不佳。治疗耐药背后的主要机制之一被认为是肿瘤内异质性。在本研究中，我们在胚胎性RMS（ERMS）细胞系和RT细胞系中研究了生肌决定因子1（MYOD1）和骨形态发生蛋白拮抗剂（NOG）标志物，以及表达MYOD1和NOG的亚群对化疗的不同反应。重要的是，我们发现这些标志物共同识别出一个对长春新碱和阿霉素具有原发性耐药的细胞亚群（MYOD1+NOG+细胞），这两种药物是ERMS和RT常用的化疗药物。化疗耐药的MYOD1+NOG+细胞表达未分化细胞的标志物，如肌细胞生成素和ID1。长春新碱与TPA/GSK126联合使用，这是一种已被证明能诱导RMS细胞系分化的药物组合，能够部分克服MYOD1/NOG细胞的化疗耐药性。
