Sources of CNS tumor heterogeneity

• DOI: 10.18632/oncoscience.60
• Publication Date: 2015-09-27T02:07:00Z
• Authors: Fuyi Chen; Albert Becker; Joseph LoTurco
• Keywords: 0301 basic medicine; 03 medical and health sciences; 0302 clinical medicine; 10. No inequality; 3. Good health

Central nervous system tumors are marked with high intra- and inter-tumoral heterogeneity. For instance, an integrative large scale gene expression study performed in 2010 revealed 4 subtypes glioblastoma multiforme (GBM) differential responses to treatment prognosis [1]. A more comprehensive GBM classification based on combination of epigenetics, copy number variation, genetic mutation analysis has led identification as many 6 subgroups [2].

Two, not mutually exclusive, general models have been proposed explain tumor heterogeneity [3]. The model proposes that different mutations lead formation, while the cell origin explains arising from types. There is experimental evidence supporting both models. example, 3 distinctly CNS types can be induced by infection postnatal mouse neural stem cells virus containing V12HRAS c-MYC depending sequence which oncogenes introduced [4]. Similarly, RNA interference (RNAi) knock down NF1 p53 GFAP+ or SynI+ induces mesenchymal GBM, whereas same RNAi Nestin+ GBM[5]. GMB also indicates transcipt profiles similar [1].

To fully explore causes diversity, it desirable2 animal insult conveniently independently manipulated. To achieve this, we recently developed a central rat multiple expressed selected populations at times brain development [6]. In this model, used piggyBac transposon [7] stably integrate into defined utero electroporation (IUE). Using evaluated contribution heterogeneity.

To test whether oncogenic event different, but closely related, population gives rise tumors, directed HRasV12/AKT disparate radial glia lineage promoters ubiquitously active (CAG promoter), astrocyte selective GFAP (glial fibrillary acidic protein) promoter oligodendrocytes MBP (myelin basic promoter. We showed under CAG (WHO grade 4). However, controlled anaplastic oligoastrocytoma 3). further these differed histology molecular signature. These results indicate events occurring cellular types.

We next investigated phenotype could modified neurogenic bHLH family protein Neurogenin2 (Ngn2) Neural differentiation 1 (NeuroD1). Members well known important roles cell-type determination normal development. Expression either Ngn2 NeuroD1 along resulted atypical teratoid rhabdoid like (ATRT like) tumor, type previously observed after alone. tested phenotypic transformation ATRT was due transient factors cells. Our data glia, prior able induce formation. may expressing levels individual transcription very types.

The main advantage IUE method allows for introduction transgenes independent promoters. co-expression rates allowed us direct subpopulations sequence. system, demonstrated use multi-color fluorescent produce clonal readout growth invasion. several additional features make useful other applications investigating biology. piggyBac- approach applied species than rodent extending biology species, such ferret. Combination piggyBac-IUE existing transgenic potentially broaden utility approaches. Also multicolor labeling facilitate vivo imaging clonally related functionalities should platform screening potential modifiers studying how