Characterization of brain tumor initiating cells isolated from an animal model of CNS primitive neuroectodermal tumors

Sergey Malchenko*, Simone Trieger Sredni, Jerusha Boyineni, Yingtao Bi, Naira V. Margaryan, Maheedhara R. Guda, Yulia Kostenko, Tadanori Tomita, Ramana V Davuluri, Kiran Velpula, Mary J.C. Hendrix, Marcelo B. Soares

*Corresponding author for this work

Research output: Contribution to journalArticle

3 Scopus citations

Abstract

CNS Primitive Neuroectodermal tumors (CNS-PNETs) are members of the embryonal family of malignant childhood brain tumors, which remain refractory to current therapeutic treatments. Current paradigm of brain tumorigenesis implicates brain tumor-initiating cells (BTIC) in the onset of tumorigenesis and tumor maintenance. However, despite their significance, there is currently no comprehensive characterization of CNS-PNETs BTICs. Recently, we described an animal model of CNS-PNET generated by orthotopic transplantation of human Radial Glial (RG) cells - the progenitor cells for adult neural stem cells (NSC) - into NOD-SCID mice brain and proposed that BTICs may play a role in the maintenance of these tumors. Here we report the characterization of BTIC lines derived from this CNS-PNET animal model. BTIC's orthotopic transplantation generated highly aggressive tumors also characterized as CNS-PNETs. The BTICs have the hallmarks of NSCs as they demonstrate self-renewing capacity and have the ability to differentiate into astrocytes and early migrating neurons. Moreover, the cells demonstrate aberrant accumulation of wild type tumor-suppressor protein p53, indicating its functional inactivation, highly up-regulated levels of onco-protein cMYC and the BTIC marker OCT3/4, along with metabolic switch to glycolysis - suggesting that these changes occurred in the early stages of tumorigenesis. Furthermore, based on RNA- and DNA-seq data, the BTICs did not acquire any transcriptome-changing genomic alterations indicating that the onset of tumorigenesis may be epigenetically driven. The study of these BTIC selfrenewing cells in our model may enable uncovering the molecular alterations that are responsible for the onset and maintenance of the malignant PNET phenotype.

Original languageEnglish (US)
Pages (from-to)13733-13747
Number of pages15
JournalOncotarget
Volume9
Issue number17
DOIs
StatePublished - Jan 1 2018

Keywords

  • Brain tumor-initiating cells
  • CNS-PNET animal model
  • Gene signature
  • RNA/DNA-seq
  • Radial glia

ASJC Scopus subject areas

  • Oncology

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    Malchenko, S., Sredni, S. T., Boyineni, J., Bi, Y., Margaryan, N. V., Guda, M. R., Kostenko, Y., Tomita, T., Davuluri, R. V., Velpula, K., Hendrix, M. J. C., & Soares, M. B. (2018). Characterization of brain tumor initiating cells isolated from an animal model of CNS primitive neuroectodermal tumors. Oncotarget, 9(17), 13733-13747. https://doi.org/10.18632/oncotarget.24460