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In silico discovery of a FOXM1 driven embryonal signaling pathway in therapy resistant neuroblastoma tumors

Suzanne Vanhauwaert (UGent) , Bieke Decaesteker (UGent) , Sara De Brouwer (UGent) , Carina Leonelli (UGent) , Kaat Durinck (UGent) , Pieter Mestdagh (UGent) , Jo Vandesompele (UGent) , Karen Sermon, Geertrui Denecker (UGent) , Christophe Van Neste (UGent) , et al.
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Abstract
Chemotherapy resistance is responsible for high mortality rates in neuroblastoma. MYCN, an oncogenic driver in neuroblastoma, controls pluripotency genes including LIN28B. We hypothesized that enhanced embryonic stem cell (ESC) gene regulatory programs could mark tumors with high pluripotency capacity and subsequently increased risk for therapy failure. An ESC miRNA signature was established based on publicly available data. In addition, an ESC mRNA signature was generated including the 500 protein coding genes with the highest positive expression correlation with the ESC miRNA signature score in 200 neuroblastomas. High ESC m(i)RNA expression signature scores were significantly correlated with poor neuroblastoma patient outcome specifically in the subgroup of MYCN amplified tumors and stage 4 nonamplified tumors. Further data-mining identified FOXM1, as the major predicted driver of this ESC signature, controlling a large set of genes implicated in cell cycle control and DNA damage response. Of further interest, re-analysis of published data showed that MYCN transcriptionally activates FOXM1 in neuroblastoma cells. In conclusion, a novel ESC m(i)RNA signature stratifies neuroblastomas with poor prognosis, enabling the identification of therapy-resistant tumors. The finding that this signature is strongly FOXM1 driven, warrants for drug design targeted at FOXM1 or key components controlling this pathway.
Keywords
DNA-DAMAGE RESPONSE, STEM-CELLS, GENE-EXPRESSION, TARGETING MYCN, B-MYB, CANCER, MICRORNAS, BINDING, TRANSCRIPTION, LANDSCAPE

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Chicago
Vanhauwaert, Suzanne, Bieke Decaesteker, Sara De Brouwer, Carina Leonelli, Kaat Durinck, Pieter Mestdagh, Jo Vandesompele, et al. 2018. “In Silico Discovery of a FOXM1 Driven Embryonal Signaling Pathway in Therapy Resistant Neuroblastoma Tumors.” Scientific Reports 8.
APA
Vanhauwaert, Suzanne, Decaesteker, B., De Brouwer, S., Leonelli, C., Durinck, K., Mestdagh, P., Vandesompele, J., et al. (2018). In silico discovery of a FOXM1 driven embryonal signaling pathway in therapy resistant neuroblastoma tumors. SCIENTIFIC REPORTS, 8.
Vancouver
1.
Vanhauwaert S, Decaesteker B, De Brouwer S, Leonelli C, Durinck K, Mestdagh P, et al. In silico discovery of a FOXM1 driven embryonal signaling pathway in therapy resistant neuroblastoma tumors. SCIENTIFIC REPORTS. 2018;8.
MLA
Vanhauwaert, Suzanne, Bieke Decaesteker, Sara De Brouwer, et al. “In Silico Discovery of a FOXM1 Driven Embryonal Signaling Pathway in Therapy Resistant Neuroblastoma Tumors.” SCIENTIFIC REPORTS 8 (2018): n. pag. Print.
@article{8584074,
  abstract     = {Chemotherapy resistance is responsible for high mortality rates in neuroblastoma. MYCN, an oncogenic driver in neuroblastoma, controls pluripotency genes including LIN28B. We hypothesized that enhanced embryonic stem cell (ESC) gene regulatory programs could mark tumors with high pluripotency capacity and subsequently increased risk for therapy failure. An ESC miRNA signature was established based on publicly available data. In addition, an ESC mRNA signature was generated including the 500 protein coding genes with the highest positive expression correlation with the ESC miRNA signature score in 200 neuroblastomas. High ESC m(i)RNA expression signature scores were significantly correlated with poor neuroblastoma patient outcome specifically in the subgroup of MYCN amplified tumors and stage 4 nonamplified tumors. Further data-mining identified FOXM1, as the major predicted driver of this ESC signature, controlling a large set of genes implicated in cell cycle control and DNA damage response. Of further interest, re-analysis of published data showed that MYCN transcriptionally activates FOXM1 in neuroblastoma cells. In conclusion, a novel ESC m(i)RNA signature stratifies neuroblastomas with poor prognosis, enabling the identification of therapy-resistant tumors. The finding that this signature is strongly FOXM1 driven, warrants for drug design targeted at FOXM1 or key components controlling this pathway.},
  articleno    = {17468},
  author       = {Vanhauwaert, Suzanne and Decaesteker, Bieke and De Brouwer, Sara and Leonelli, Carina and Durinck, Kaat and Mestdagh, Pieter and Vandesompele, Jo and Sermon, Karen and Denecker, Geertrui and Van Neste, Christophe and Speleman, Franki and De Preter, Katleen},
  issn         = {2045-2322},
  journal      = {SCIENTIFIC REPORTS},
  language     = {eng},
  pages        = {11},
  title        = {In silico discovery of a FOXM1 driven embryonal signaling pathway in therapy resistant neuroblastoma tumors},
  url          = {http://dx.doi.org/10.1038/s41598-018-35868-5},
  volume       = {8},
  year         = {2018},
}

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