Definition of Genetic Events Directing the Development of Distinct Types of Brain Tumors from Postnatal Neural Stem/Progenitor Cells

Abstract

Although brain tumors are classified and treated based upon their histology, the molecular factors involved in the development of various tumor types remain unknown. In this study, we show that the type and order of genetic events directs the development of gliomas, central nervous system primitive neuroectodermal tumors, and atypical teratoid/rhabdoid-like tumors from postnatal mouse neural stem/progenitor cells (NSC/NPC). We found that the overexpression of specific genes led to the development of these three different brain tumors from NSC/NPCs, and manipulation of the order of genetic events was able to convert one established tumor type into another. In addition, loss of the nuclear chromatin-remodeling factor SMARCB1 in rhabdoid tumors led to increased phosphorylation of eIF2α, a central cytoplasmic unfolded protein response (UPR) component, suggesting a role for the UPR in these tumors. Consistent with this, application of the proteasome inhibitor bortezomib led to an increase in apoptosis of human cells with reduced SMARCB1 levels. Taken together, our findings indicate that the order of genetic events determines the phenotypes of brain tumors derived from a common precursor cell pool, and suggest that the UPR may represent a therapeutic target in atypical teratoid/rhabdoid tumors.

Contribution of Tumor Heterogeneity in a New Animal Model of CNS Tumors

“…Hertwig et al (33) has reported that a panel of 7 signature genes can be used in error freely classification of three CNS tumors: glioma, PNET and ATRT. We therefore assessed the expression of this panel of 7 genes in the tumors induced by HRasV12/AKT in combination with Ngn2.…”

“…Overwhelming experimental and clinical evidence show that different genetic mutations result in different tumor types including different CNS tumor types (37). For example, Hertwig et al (33) showed that infection of postnatal mouse neural stem cells with viruses containing V12HRAS or c-MYC could result in formation of 3 different tumor types depending upon the combination and sequence in which oncogenes were introduced. Similarly, Jacques et al (38) showed that different combinations of conditional genetic deletions in p53, Rb and PTEN in mouse subventricular zone neural stem cells could induce formation of either PNET or glioma.…”

“…INI1 knockout mice develop tumors but these do not appear to be ATRT (49). Hertwig et al (33) showed that transplantation of NSC/NPCs serially infected with c-MYC and V12HRAS could generate ARTR like tumors with gene expression profiles similar to human ATRT suggesting that in rodent models additional mutation types can lead to ATRT. Similarly, we demonstrated in this study that ATRT like tumors are generated by HRasV12 and AKT transfection of neocortical radial glia, but only when co-expressed with the bHLH transcription factors Ngn2 or NeuroD1, two genes that on their own are non-oncogenic.…”

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“…SMARCB1 loss profoundly activates the transcription factor MYC, resulting in significant upregulation of protein anabolism which can render cells susceptible to disruption of their proteostatic machinery [7,8]. To further investigate the biological mechanisms underlying this finding, we developed Smarcb1-deficient embryonic mosaic mouse models of MRT and found that SMARCB1-deficient cancer cells show profound evidence of endoplasmic reticulum (ER) stress, including ER swelling, reticulophagy, alterations in the ERribosome interfase, and prominent accumulation of cytoplasmic protein aggregates.…”

Sources of CNS tumor heterogeneity

“…There is experimental evidence supporting both models. For example, 3 distinctly different CNS tumor types can be induced by infection of postnatal mouse neural stem cells with virus containing V12HRAS and c-MYC depending on the combination and sequence in which oncogenes are introduced [ 4 ]. Similarly, RNA interference (RNAi) knock down of NF1 and p53 in GFAP+ or SynI+ cells induces mesenchymal GBM, whereas the same RNAi in Nestin+ cells induced neural GBM[ 5 ].…”