Characterization of brain tumor initiating cells isolated from an animal model of CNS primitive neuroectodermal tumors
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Sergey Malchenko1, Simone T. Sredni2,3,*, Jerusha Boyineni1,*, Yingtao Bi4,5, Naira V. Margaryan6, Maheedhara R. Guda1, Yulia Kostenko1, Tadanori Tomita2, Ramana V. Davuluri4, Kiran Velpula1, Mary J.C. Hendrix6,7 and Marcelo B. Soares1
1Department of Cancer Biology & Pharmacology, University of Illinois College of Medicine, Peoria, Illinois, United States of America
2Department of Surgery, Division of Pediatric Neurosurgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States of America
3Cancer Biology and Epigenomics Program at The Stanley Manne Children’s Research Institute, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, Illinois, United States of America
4Department of Preventive Medicine, Division of Health and Biomedical Informatics, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States of America
5AbbVie Bioresearch Center, Worcester, Massachusetts, United States of America
6Department of Biochemistry, Robert C. Byrd Health Sciences Center and Cancer Institute, West Virginia University, Morgantown, West Virginia, United States of America
7Department of Biology, Shepherd University, Shepherdstown, West Virginia, United States of America
*These authors have contributed equally to this work
Sergey Malchenko, email: [email protected]
Keywords: CNS-PNET animal model; radial glia; brain tumor-initiating cells; RNA/DNA-seq; gene signature
Received: December 10, 2017 Accepted: January 30, 2018 Published: February 09, 2018
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 self-renewing cells in our model may enable uncovering the molecular alterations that are responsible for the onset and maintenance of the malignant PNET phenotype.
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