Abstract
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.
Highlights
Rhabdomyosarcoma (RMS) and rhabdoid tumors (RT) are rare soft-tissue malignancies with the highest incidence in infants, children, and adolescents
RMS tumors have been reported to be positive for myogenic determination factor 1 (MYOD1) with marked heterogeneity between cells [18], while RT are believed to be negative for MYOD1 [20, 21]
Since RMS tumor cells demonstrate an intratumor differential response to these agents, a degree of heterogeneity among tumor cells can be postulated. In this in vitro study, Vincristine and Doxorubicin chemoresistant subpopulations were identified as cells expressing the markers MYOD1 and NOG in two patient-derived soft-tissue tumor models (A204, a rhabdoid tumor cell line, and RD, an embryonal rhabdomyosarcoma cell line)
Summary
Rhabdomyosarcoma (RMS) and rhabdoid tumors (RT) are rare soft-tissue malignancies with the highest incidence in infants, children, and adolescents. RMS rarely occurs in adults, the outcomes are significantly worse [1]. When ERMSs are advanced, recurrent, and/or metastatic, they are classified as high risk and exhibit poor response to treatment (chemoresistance), having a progression-free survival less than 1.5 years with a 5-year survival rate as low as 20% [3,4,5]. In both children and adults, RMS and RT are treated with a combination of therapies including surgery, radiation, and chemotherapy [6, 7]
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