TY - JOUR
T1 - De novo regulation of RD3 synthesis in residual neuroblastoma cells after intensive multi-modal clinical therapy harmonizes disease evolution
AU - Somasundaram, Dinesh Babu
AU - Subramanian, Karthikeyan
AU - Aravindan, Sheeja
AU - Yu, Zhongxin
AU - Natarajan, Mohan
AU - Herman, Terence
AU - Aravindan, Natarajan
N1 - Funding Information:
The authors acknowledge the NB specimen providers: Department of Pathology, University of Oklahoma Health Sciences Center; Cooperative Human Tissue Network (CHTN), which is funded by the National Cancer Institute (NCI), and; Oregon Health and Science University Biospecimen core. The authors acknowledge with gratitude the Children’s Oncology Group (COG) Cell Culture and Xenograft Repository for the stage 4 MYCN-na NB cell lines. The authors acknowledge the SCC Cancer Tissue pathology core for all TMA and IHC services, the SCC Cancer Functional Genomics core for high-content confocal imaging, the SCC Molecular Imaging core for all in vivo non-invasive fluorescent imaging, and the OUHSC Flow Cytometry and Imaging core for the cell sorting services. The authors also acknowledge the OUHSC Staff Editor (Ms. Kathy Kyler) for the help in critically reviewing this manuscript. The authors are supported by the research funding from the National Institutes of Health (NIH 1P20GM103639-01) from the COBRE Program of NIH; Stephenson Cancer Center - Cancer Biology Program (NCI- P30CA225520 – SCC-CCSG) and Presbyterian Health Foundation Seed funds, and; OUHSC Department of Radiation Oncology Research Development Funds.
Publisher Copyright:
© 2019, The Author(s).
PY - 2019/12/1
Y1 - 2019/12/1
N2 - Most high-risk neuroblastomas that initially respond to therapy will ultimately relapse. Currently, no curative treatment is available. Acquired genetic/molecular rearrangement in therapy-resistant cells contributes to tumor relapse. Recently, we identified significant RD3 loss in progressive disease (PD) and defined its association with advanced disease-stage and poor clinical outcomes. Here, we investigated whether RD3 loss is an acquired process in cells that survive intensive multi-modal clinical therapy (IMCT) and its significance in disease evolution. RD3 status (mRNA, protein) during diagnosis (Dx) and PD after IMCT was investigated in NB patient cohort (n = 106), stage-4 NB cell lines (n = 15) with known treatment status and validated with independent data from another set of 15 cell-lines. Loss of RD3 in metastatic disease was examined using a mouse model of PD and metastatic-site-derived aggressive cells (MSDACs) ex vivo. RD3 silencing/expression assessed changes in metastatic state. Influence of RD3 loss in therapy resistance was examined through independent in vitro and in vivo studies. A significant loss of RD3 mRNA and protein was observed in resistant cells derived from patients with PD after IMCT. This is true to the effect within and between patients. Results from the mouse model identified significant transcriptional/translational loss of RD3 in metastatic tumors and MSDACs. RD3 re-expression in MSDACs and silencing RD3 in parental cells defined the functional relevance of RD3-loss in PD pathogenesis. Analysis of independent studies with salvage therapeutic agents affirmed RD3 loss in surviving resistant cells and residual tumors. The profound reductions in RD3 transcription indicate the de novo regulation of RD3 synthesis in resistant cells after IMCT. Defining RD3 loss in PD and the benefit of targeted reinforcement could improve salvage therapy for progressive neuroblastoma.
AB - Most high-risk neuroblastomas that initially respond to therapy will ultimately relapse. Currently, no curative treatment is available. Acquired genetic/molecular rearrangement in therapy-resistant cells contributes to tumor relapse. Recently, we identified significant RD3 loss in progressive disease (PD) and defined its association with advanced disease-stage and poor clinical outcomes. Here, we investigated whether RD3 loss is an acquired process in cells that survive intensive multi-modal clinical therapy (IMCT) and its significance in disease evolution. RD3 status (mRNA, protein) during diagnosis (Dx) and PD after IMCT was investigated in NB patient cohort (n = 106), stage-4 NB cell lines (n = 15) with known treatment status and validated with independent data from another set of 15 cell-lines. Loss of RD3 in metastatic disease was examined using a mouse model of PD and metastatic-site-derived aggressive cells (MSDACs) ex vivo. RD3 silencing/expression assessed changes in metastatic state. Influence of RD3 loss in therapy resistance was examined through independent in vitro and in vivo studies. A significant loss of RD3 mRNA and protein was observed in resistant cells derived from patients with PD after IMCT. This is true to the effect within and between patients. Results from the mouse model identified significant transcriptional/translational loss of RD3 in metastatic tumors and MSDACs. RD3 re-expression in MSDACs and silencing RD3 in parental cells defined the functional relevance of RD3-loss in PD pathogenesis. Analysis of independent studies with salvage therapeutic agents affirmed RD3 loss in surviving resistant cells and residual tumors. The profound reductions in RD3 transcription indicate the de novo regulation of RD3 synthesis in resistant cells after IMCT. Defining RD3 loss in PD and the benefit of targeted reinforcement could improve salvage therapy for progressive neuroblastoma.
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U2 - 10.1038/s41598-019-48034-2
DO - 10.1038/s41598-019-48034-2
M3 - Article
C2 - 31409909
AN - SCOPUS:85070763855
SN - 2045-2322
VL - 9
JO - Scientific Reports
JF - Scientific Reports
IS - 1
M1 - 11766
ER -